J Am Soc Nephrol 11: 152–176, 2000
REVIEW
Chemokines, Chemokine Receptors, and Renal Disease: From
Basic Science To Pathophysiologic and Therapeutic Studies
STEPHAN SEGERER, PETER J. NELSON, and DETLEF SCHLÖNDORFF
Medizinische Poliklinik, Klinikum Innenstadt der Ludwig-Maximilians-Universität, Munich, Germany.
Abstract. Leukocyte trafficking from peripheral blood into
affected tissues is an essential component of the inflammatory
reaction to virtually all forms of injury and is an important
factor in the development of many kidney diseases. Advances
in the past few years have highlighted the central role of a
family of chemotactic cytokines called chemokines in this
process. Chemokines help to control the selective migration
“In the injured glomerulus increased capillary permeability is
associated, as in other examples of inflammation, with a so-
called increased stickiness of the endothelial cells. Circulating
polymorphonuclear neutrophils adhere to these sticky walls
and thus accumulate in the glomerulus” (1). This observation
by Jones in the early 1950s describes a fundamental premise of
this review. Namely, what makes the endothelium “sticky” at
a specific site of the vasculature to a specific subset of inflam-
matory cells and then controls their subsequent transmigration
and entry into renal tissue? Developments over the past 10
years have highlighted the roles of specific adhesion molecules
and chemokines in this process (2– 6).
Chemokines are a family of chemotactic cytokines that were
first identified on the basis of their ability to induce the
migration of different cell types, particularly those of lymphoid
origin (7–9). A wealth of data has demonstrated that chemo-
kines working in concert with selectins and integrins act as
directional signals to sort and direct effector leukocyte migra-
tion (4,10,11). In addition, chemokines have also been shown
to activate leukocytes, influence hematopoiesis, and modulate
angiogenesis (12–14).
The receptors for chemokines are expressed in a cell type-
specific manner and are restricted primarily to subsets of
leukocytes (15). The discovery that some chemokine receptors
act as coreceptors for HIV entry into target cells has acceler-
ated research in this field (16 –22). Advances over the past few
Received July 28, 1999. Accepted October 2, 1999.
This review is dedicated to our collaborators in Japan, the United States, and
Europe.
Correspondence to Dr. Detlef Schlöndorff, Medizinische Poliklinik, Klinikum
Innenstadt der Ludwig-Maximilians-Universität, Pettenkoferstrasse 8a, 80336
Munich, Germany. Phone: ⫹49 89 5160 3500; Fax: ⫹49 89 5160 4439;
E-mail: sdorff@pk-i.med.uni-muenchen.de
1046-6673/1101-0152
Journal of the American Society of Nephrology
Copyright © 2000 by the American Society of Nephrology
and activation of inflammatory cells into injured renal tissue.
Chemokines and their receptors are expressed by intrinsic renal
cells as well as by infiltrating cells during renal inflammation.
This study summarizes the in vitro and in vivo data on chemo-
kines and chemokine receptors in renal diseases with a special
focus on potential therapeutic effects on inflammatory pro-
cesses.
years have included the discovery of new chemokines, recep-
tors, and antagonists, and a greater appreciation for the diverse
biologic functions displayed by this cytokine family (15,23–
25). Several recent reviews have dealt with the basic biology
and the roles of chemokines in various disease processes (2–
4,9,15,26 –28). This review will focus on the biology of the
chemokine and chemokine receptor families in the context of
renal diseases.
Chemokines: Classification and Mechanisms of
Action
The Chemokine Superfamily Is Comprised of Four
Members
More than 40 chemokines and 17 chemokine receptors have
been described to date, with additional candidates currently
under investigation (Tables 1 and 2) (3,4,15,27,29). Chemo-
kines are characterized by a series of shared structural deter-
minants including conserved cysteine residues that form disul-
fide bonds in the chemokine tertiary structure (29,30). The
chemokines were initially subdivided into two branches based
on the position of these cysteine residues (9,15,27). In the CXC
chemokine family, the first two cysteine residues in the pri-
mary amino acid sequence are separated by a single amino acid
(X represents any intervening amino acid residue). In the CC
subfamily, the cysteine residues lie next to each other. Al-
though most of the chemokines belong to one of these two
classes, two additional branches of the chemokine superfamily
each containing a single member have been described in recent
years (31,32). The C chemokine lymphotactin lacks both the
first and third cysteine in the “4 cysteine motif,” but shares
homology at its carboxyl end with the CC chemokines (32).
Fractalkine has three intervening amino acids between the first
two cysteine residues (31). This CX3C chemokine is tethered
directly to the cell membrane via a long mucin stalk and has
recently been shown to combine the function of a chemokine
and an adhesion molecule (33).
J Am Soc Nephrol 11: 152–176, 2000 Chemokines, Chemokine Receptors, and Renal Disease 153

Some CXC chemokines display an additional structural des-

HCC, hemofiltrate CC chemokine; MCP, monocyte chemoattractant protein; MIP, macrophage inflammatory protein; RANTES, regulated upon activation, normal T cell expressed
CCR10
MCP-1
MCP-3
ignation, namely, the amino acid motif E-L-R-CXC (glutamic
acid-leucine-arginine-cysteine-X-cysteine) just proximal to

and secreted; MDC, macrophage-derived chemokine; TARC, thymus and activation-regulated chemokine; LARC, liver and activation-regulated chemokine; ELC, EBI1 ligand
their first two cysteine residues. The E-L-R-CXC chemokines
TECK

CCR9
act primarily as neutrophil chemoattractants (30). In contrast,

T cell
the CXC chemokines that lack the E-L-R motif bind different
CXC receptors and are active on lymphocytes (9,30).
Monocyte Chemokines are involved in more than the control of cell
TCA-3

migration. Melanoma growth stimulating activity/growth-re-

CCR8
I-309,

lated oncogene-␣ (GRO-␣) was originally identified as an

autocrine growth factor for malignant melanoma cells (30,34).
Interferon-inducible protein-10 (IP-10) has been shown to in-
Dendritic cell

T cell (naive)

duce the proliferation of mesangial cells (35). Interleukin-8

(mature)

(IL-8) can cause release of granules and respiratory burst in

neutrophils (12). Regulated upon activation, normal T cell
CCR7

B cell
ELC
SLC

expressed and secreted (RANTES) can induce eosinophil and

basophil degranulation, respiratory burst in eosinophils (36),
and has been shown to augment T cell proliferation (37).
Dendritic cell
(immature)

Platelet factor 4 (PF4) inhibits megakaryopoiesis (38) and can

be bactericidal (39). In addition, some chemokines are in-
(LARC)
MIP-3␣

B cells
T cells
CCR6

volved in hematopoiesis (13,40 – 42). A novel role for some

classes of chemokines and their receptors as anti-inflammatory
mediators has recently been suggested (43). The CXC chemo-
Dendritic cell

kines IL-8, epithelial cell-derived neutrophil attractant 78

(immature)

Natural killer

(ENA-78), and GRO-␣,␤,␥, which contain the E-L-R-CXC

Monocytes
Th1 T cell
RANTES
MIP-1␣
MIP-1␤

motif, have been shown to act as angiogenic agents (44), while

MCP-2

CCR5

cell

PF4, IP-10, monokine induced by interferon-␥ (MIG), and

stromal cell-derived factor-1 (SDF-1), which lack this motif,
chemokine; SLC, secondary lymphoid tissue chemokine; TECK, thymus-expressed chemokine.

can act as angiostatic factors (14). During embryogenesis,

Dendritic cell

wound healing, chronic inflammation, and tumor growth, the

(mature)

Th2 T cell

expression of chemokines may help to determine the micro-

Basophil

vascularization within the tissue.

TARC

CCR4
MDC
Table 1. CC chemokine receptors, their tissue distribution, and ligandsa

Regulation of Chemokine Expression

Chemokines are regulated at transcriptional, posttranscrip-
Dendritic cell

tional, translational, and posttranslational levels (2). Many, but

Eosinophil

Th2 T cell
Eotaxin-2
RANTES

not all, of the proinflammatory chemokines are induced by

Basophil
Eotaxin
MCP-3
MCP-4

IL-1␤ or tumor necrosis factor-␣ (TNF-␣). Some CXC che-

CCR3

mokines (MIG, IP-10) were initially identified on the basis of

their specific upregulation by interferon-␥ (IFN-␥) (45). Other
chemokines, especially those that play a role in normal leuko-
Dendritic cell

Natural killer
(immature)

cyte trafficking, appear to be constitutively expressed (SDF-1,

Monocyte

Basophil

B cell attracting chemokine-1, thymus-expressed chemokine,

MCP-1
MCP-2
MCP-3
MCP-4
MCP-5
CCR2

T cell

cell

secondary lymphoid tissue chemokine, EBI1 ligand chemo-

kine, hemofiltrate CC chemokine-1, liver and activation-regu-
lated chemokine) (28).
Dendritic cell
(immature)

Some of the best-studied proinflammatory chemokines (e.g.,

Neutrophil
Eosinophil
Th1 T cell

Mesangial

IL-8, RANTES, monocyte chemoattractant protein-1 [MCP-

Monocyte
RANTES
MIP-1␣
MCP-2
MCP-3

1]) are controlled at the transcriptional level by the transcrip-

HCC-1

CCR1

cell

tion factors nuclear factor-␬B (NF-␬B), CAAT enhancer bind-

ing protein, and activator protein-1 (21,46,47). Their activation
requires a complex cascade of steps including phosphorylation
expressing

by multiple kinases and phosphatases, degradation of transcrip-

Chemokine

Chemokine

cell type
receptor

tional inhibitors, translocation of transcription factors from

Receptor

cytoplasm to nucleus, etc. (4). These signaling pathways can be

different for each stimulus and transcription factor and are
a

further complicated by “cross-talk” between the various path-

154 Journal of the American Society of Nephrology J Am Soc Nephrol 11: 152–176, 2000

Table 2. DARC, CXC, CX3C, and C chemokine receptors, their tissue distribution, and ligandsa

Chemokine IL-8 IL-8 I-TAC SDF-1␣ BCA-1 Lymphotactin Fractalkine CC, CXC
GCP-2 GCP-2 IP-10 SDF-1␤ (const. (const. chemokines
GRO-␣ MIG expr.) expr.) (RANTES,
GRO-␤ MCP-1, GRO-␣,
GRO-␥ IL-8, NAP-2,
ENA-78 PF4)
NAP-2
LIX
Chemokine CXCR1 CXCR2 CXCR3 CXCR4 CXCR5 XCR1 CX3CR1 DARC
receptor
Receptor Neutrophil Neutrophil Th1 T cell T cell (naive) T cell T cell Natural killer Red blood cells
expressing Dendritic cell B cell Dendritic cell B cell cell Endothelial cells
cell type (immature) Natural killer (mature) T cell
cell Monocyte
B cell

DARC, Duffy antigen receptor for chemokines; IL, interleukin; GCP, granulocyte chemotactic protein; GRO, growth-related oncogene;
ENA-78, epithelial cell-derived neutrophil attractant 78; NAP-2, neutrophil-activating peptide-2; LIX, lipopolysaccharide-induced CXC
chemokine; I-TAC, interferon-inducible T cell alpha chemoattractant; IP-10, interferon-inducible protein 10; MIG, monokine induced by
interferon-␥; SDF, stromal cell-derived factor; const. expr., constitutive expression; BCA-1, B cell-attracting chemokine 1; PF4, platelet
factor 4. Other abbreviations as in Table 1.

ways (48). Although at first glance this may appear to be an
unnecessarily complicated system, it allows the fine-tuning and
integration of the multiple signals required for a complex
signal- and tissue-specific biologic response. These biochem-
ical events are potential targets for therapeutic intervention.
For example, glucocorticoids interfere with NF-␬B activation
(49,50). Similarly, agents that influence cAMP levels often
modulate the stimulatory signals for chemokine expression
(51–53). The inhibition of chemokine expression seen after
treatment with free radical scavengers may be due to interfer-
ence with NF-␬B activation, but may also involve other redox-
related steps (54).
Selective Expression of Chemokine Receptors
Contributes to Cell Specificity of Chemokine Action
The biologic actions of chemokines (Table 3) are mediated
through a family of G protein-coupled receptors with seven
transmembrane domains (4,25,55,56). The nomenclature used
to describe these receptors is based on the class of chemokine
ligands that interact with the receptor (i.e., C, CC, CXC, and
CX3C receptors) (27). Many chemokines bind to several different
receptors (Tables 1 and 2) (57). The differential expression of the
receptors by distinct leukocyte subsets is an important component
of the specificity of chemokine action (27,58). The complexity
and apparent redundancy of the system is thought to provide a
high degree of effectiveness and flexibility in vivo (57).
Binding of a chemokine to its receptor activates a signal
transduction cascade leading to activation of phospholipase
C␣1 and ␣2, and the production of inositol (1,4,5)-trisphos-
phate and diacylglycerol (2,4). In addition, a rapid and tran-
sient increase in intracellular calcium, and the activation of
protein kinase C are observed (59 – 61). A variety of kinases
may be involved in signal transduction, including serine/thre-
Table 3. Principles of chemokine action
Chemokines released by stimulated cells act locally
Chemokines are produced by intrinsic cells as well as
by infiltrating cells
Chemokines act through G protein-coupled seven
transmembrane receptors and induce calcium influx
Chemokine receptor expression is cell-specific
Chemokines bind to proteoglycans and extracellular
matrix
Chemokines induce haptotaxis (cell migration along
surface gradients)
Chemokines can activate adhesion molecules
Chemokines can induce oxygen burst and the release of
granules and proteinases by leukocytes
Chemokines control aspects of immunomodulation,
angiogenesis, hematopoiesis, and development
onine kinases (e.g., members of the mitogen-activated protein
kinase cascade) as well as tyrosine protein kinases (59). The
various stimulatory and inhibitory pathways involved in these
activation cascades are providing insight into the design of
potential pharmacologic agents.
The Duffy Antigen Receptor for Chemokines
The Duffy antigen receptor for chemokines (DARC) is a
“promiscuous” receptor-like structure that binds the CXC fam-
ily proteins IL-8 (62,63), GRO (63), PF4 (64), neutrophil
activating peptide-2, as well as the CC chemokines MCP-1
(62,63) and RANTES (63). DARC, first identified as the Duffy
blood group antigen, is expressed on erythrocytes and endo-
J Am Soc Nephrol 11: 152–176, 2000 Chemokines, Chemokine Receptors, and Renal Disease 155

Table 4. CXC chemokines produced by renal cellsa

IL-8 GRO CINC

⫹ ⫺ ⫹ ⫺ ⫹ ⫺

Mesangial cells TNF-␣ (102, 221, 222) Dexamethasone (222) IL-1␤ (127) Dexamethasone (127) IL-1␤ (224, 225) Dexamethasone (224)
IL-1␣ (221, 222) PDTC (218) Cycloheximide (127) TNF-␣ (225) Genistein (225)
IL-1␤ (102, 112) IL-1ra LPS (225)
PMA (112)
Cross-linking of
Fc-R (223)
IgA (218)
bFGF (114)
Epithelial cells IL-1␣ (226) IFN-␥ (226)
IL-1␤ (209)
IL-17 (227)
TGF-␤1 (129)
TNF-␣ (209, 226)
LPS (209)
Porin (228)
CD40 ligand (229)
Endothelial IL-1␤ (230)
cells TNF-␣ (230)

IP-10 ENA-78 MIP-2

⫹ ⫺ ⫹ ⫺ ⫹ ⫺

Mesangial cells IL-1␤ (112) PDTC (218) IL-1␤ (225) Genistein (225)
IFN-␥ (112, 231) TNF-␣ (225)
TNF-␣ (112, 231) LPS (225)
LPS (231)
IgA (218)
ICs (231)
Epithelial cells IL-1␤ (207)
Endothelial cells TNF-␣ (232)
Interstitial cells LPS (233)
a
⫹, upregulation; ⫺, inhibition; CINC, cytokine-induced neutrophil chemoattractant; TNF-␣ tumor necrosis factor-␣; PMA, phorbol
myristate acetate; Fc-R, Fc receptor; bFGF, basic fibroblast growth factor; PDTC, pyrrolidine dithiocarbamate; LPS, lipopolysaccharide;
TGF-␤1, transforming growth factor-␤1; IFN-␥, interferon-␥. Other abbreviations as in Tables 1 and 2.

thelial cells of postcapillary venules of the kidney (64 – 66).
DARC mediates Plasmodium vivax entry into red blood cells,
and DARC-“negative” individuals (generally of central Afri-
can lineage) are resistant to this form of malaria but still
express DARC on their endothelial cells (67). At present, a
function for the erythroid-expressed form of DARC is not
known. Chemokine-induced signal transduction through
DARC has not been demonstrated, and DARC is not coupled
to G proteins. One hypothesis is that DARC may act as a
scavenger that helps to clear chemokines from the circulation
(62). DARC protein expressed on postcapillary venules may
act as a presentation-like structure for chemokines on these
surfaces, and hypothetically could contribute to induced leu-
kocyte adhesion and transmigration at these sites.
Chemokines, Chemokine Receptors, and Th1, Th2
Immune Responses
The immune system mounts distinct and selective immune
responses to different types of infection or antigenic challenge.
These responses have been termed Th1-like and Th2-like after
the two classes of T helper cells (Th) involved (68 –70). Th1
and Th2 responses appear to represent the extremes of a
spectrum of immune responses. Th1 responses are stimulated
by pathogens that invade and inhabit cells and result in acti-
vation of cytotoxic T lymphocytes and delayed-type hypersen-
sitivity. The Th1 subtype produces cytokines that stimulate
strong cellular immune responses (IFN-␥, IL-2, leukotriene A,
granulocyte macrophage colony-stimulating factor). The Th2
subtypes produce cytokines that evoke strong antibody re-
sponses (IL-3, -4, -5, -6, -10, and -13). In addition, Th2 cytokines
can inhibit the inflammatory reactions induced by Th1 cytokines.
A third subtype called Th0 secretes cytokines of both types and is
believed to give rise to the “polarized” Th1 and Th2 lineages. The
recently characterized Th3/T-regulatory-1 T cell subset is thought
to downregulate antigen-presenting cells, possibly via transform-
ing growth factor-␤ (TGF-␤) (71).
Growing evidence suggests that differential chemokine re-
ceptor expression may be crucial for the generation of a Th1-
 156

Table 5. CC chemokines produced by renal cellsa

MCP-1 RANTES MIP-1␣

⫹ ⫺ ⫹ ⫺ ⫹

Mesangial cells IFN-␣ (224) Dexamethasone (224,236) IL-1␤ (224,236,245) Dexamethasone (247) IFN-␥ (114)
IFN-␥ (53,112,234) IL-1ra (221) IFN-␣ (224) PDTC (247) TNF-␣ (114)
IL-1␣ (221) TGF-␤1 (240) IFN-␥ (112) DMTU (247)
IL-1␤ (51,102,112,115,224,234–236) PGE2 (53) TNF-␣ (114,236,245–247) Hydroxymethoxyacetophenone
IL-6 (236) DMTU (241) TNF-␤ (245) (247)
TNF-␣ (53, 102, 106, 114, 221, 234, 236, 237) TMTU (106) bFGF (114)
PMA (112,237) Genistein (52,237) LPS (245)
Phorbol esters (52) Calphostin C (239) IgG-IC (247)
Diacyglycerol (52) Herbimycin (51, 52, 237) ROS (247)
Journal of the American Society of Nephrology

bFGF (114) Tyrphostin (52,237)

C5a (238)
Crosslinking of Fc-R (223) dbcAMP (237)
FCS (112) Forskolin (53)
High glucose (239) PDTC (218)
IgG-IC (53, 105, 106, 191) NF-␬ B antisense oligo (51)
IgA (218) Nuclotide (51)
LPS (112, 224, 240) Antioxidants (54)
LIF (236) Hydroxymethocyacetophenone (106)
MMSP (241) Lovastatin (172)
Matrigel (241)
NADPH (106)
ox-LDL (242)
PDGF-AB (115)
PDGF-BB (115)
Serotonin (115)
Shiga toxin (243)
Superoxide (106, 241)
Thrombin (244)
TRAP1–7 (244)
Cryoglobulins (191)
Epithelial cells IL-1␣ (108,110) Dexamethasone (120) IFN-␥ (111) PDTC (119)
IL-1␤ (109) TGF-␤1 (129) IL-1␣ (111,248) Cycloheximide (111)
IL-17 (227) Cycloheximide (108, 116, 118) IL-4 (117) Sodium salicylate (119)
J Am Soc Nephrol 11: 152–176, 2000
J Am Soc Nephrol 11: 152–176, 2000 Chemokines, Chemokine Receptors, and Renal Disease 157

PGE2, prostaglandin E2; DMTU, dimethylthiourea; TMTU, tetramethylthiourea; NF-␬B, nuclear factor ␬B; ROS, reactive oxygen species. Other abbreviations as in Tables 1, 2, and 4.
or Th2-type immune response, because specific chemokine
receptor expression has been shown to characterize these T

AT2 receptor antagonist (122)

⫹, upregulation; ⫺, inhibition; LIF, leukemia inhibitory factor; MMSP, morphine-monocyte secretory products; ox-LDL, oxidized LDL; PDGF, platelet-derived growth factor;
helper cell subtypes (72). Th1 cells appear to preferentially
express the chemokine receptors CXCR3 and CCR5, while
Th2 cells display CCR4, CCR8, and some CCR3 (28,72,73).
The chemokine receptors expressed by different populations of
T cells may thus dictate to a significant degree the tissue
infiltration of Th1 and Th2 cells and the direction of the
eventual immune response.
This is an important issue in the interpretation of results
obtained from animal models. For example, different inbred
mouse strains often demonstrate a more pronounced Th1- or
Th2-like response. After an immunologic insult, C57BL/6
TNF-␣ (111,119,246,248)
CD40 ligand (117, 229)

mice show a more Th1-like bias compared with Balb/C mice,

which show a more Th2-like response (74,75). This can influ-
ence the composition of the cellular infiltrate and subsequently
the course of the renal disease model (75).
AngII (122)
IL-13 (117)

BSA (119)
IgG (119)

Chemokines Control Important Aspects of Acute and

Chronic Inflammation
Inflammation is a process involving changes in hemodynam-
ics, vascular reaction of endothelial cells, leukocyte adhesion,
activation, and migration (76). The nature of the inflammatory
response is dictated by the pathogenic insult. The process of
Actinomycin D (116,118)

leukocyte trafficking from the peripheral circulation into tissue

Dexamethasone (216)

Dexamethasone (126)

spaces involves a series of interactions between soluble medi-

anti-CD44 Ab (116)

p65 antisense (120)

ators and surface molecules expressed by the endothelium and

Lysine (118,120)

Genistein (216)

leukocyte, as well as subsequent interactions with the extra-

cellular matrix (77). Chemokines mediate events at multiple
stages in this process (78,79). The early events in this process
entail the rolling of leukocytes along the microvascular surface
through transient interactions between vascular addressins and
selectins (80). The addressin/selectin-dependent cell-cell inter-
action is essential in leukocyte homing and promotes transient
surface contact between the rolling leukocyte and the endothe-
lial surface. The endothelium provides a selective interface
between the peripheral circulation and extravascular space and
ultimately acts as a discriminator of leukocyte infiltration.
During inflammation, the endothelium upregulates chemo-
For chemokine receptors, see references 35, 112 and 249.

kine presentation structures (such as specific glucosaminogly-

cans), selectin ligands (addressins), selectins, and the Ig part-
Holotrans-ferrin (118)

ners of leukocyte-expressed integrins (11,81). Thus, inflamed

Apotransferrin (118)

CD40 ligand (229)

TNF-␣ (108–110)

Hyaluronan (116)

microvascular endothelium increases its capacity to bind che-

DBSA (118,120)
IFN-␥ (109,110)

LPS (109,120)

mokines and upregulates the expression of molecules required

TNF-␣ (216)

TNF-␣ (126)
TNF-␣ (232)
IL-1␤ (216)

IL-1␤ (126)
PMA (216)

for the efficient rolling and firm adhesion of leukocytes.

BSA (118)

Early in inflammation, as the microvascular endothelium

becomes activated, chemokines generated by endothelial cells,
subendothelial tissue, or released after platelet activation bind
to the “activated” endothelial surface (78,82). Thus situated
chemokines act as directional signals for leukocytes as they roll
Glomerular epithelial

across the endothelium. A notable exception appears to be

fractalkine, which is a membrane-bound chemokine that also
Endothelial cells

Interstitial cells

enables direct leukocyte adhesion via its receptor CX3CR1

(33). Chemokines can trigger activation of leukocyte-ex-
cells

pressed integrins, resulting in the arrest and firm adhesion of

leukocytes to the activated endothelial surface. Important ad-
a

hesion molecule pairs in this process include the selectins (E,

158 Journal of the American Society of Nephrology
L, and P), the Ig-like molecules intercellular adhesion mole-
cule-1 and vascular cell adhesion molecule-1, and the ␤2 and
␤1 integrins (e.g., leukocyte function-associated antigen-1 and
very late antigen-4) (80). (Note: The nomenclature of these
factors is often confusing as it reflects the manner in which the
proteins were first identified rather than their structural char-
acteristics.)
After firm adhesion, leukocytes undergo spreading, diape-
desis, extravasation, and migration into interstitial spaces. Al-
though some chemokines are important for the control of
leukocyte arrest, other chemokines appear to influence the
subsequent events associated with leukocyte emigration. Leu-
kocyte emigration in vivo occurs in a complex background of
chemotactic signals where several receptors may be activated
simultaneously or successively. Thus, the migrating leukocyte
must distinguish among the various chemotactic signals within
the three-dimensional environment of the tissue to move both
up and down gradients to eventually reach the site of inflam-
mation (21,83)
Chemokines May Play a Role in the Resolution or
Progression of Inflammatory Processes
As leukocytes reach the site of inflammation and undergo
activation, they can produce additional proinflammatory fac-
tors resulting in propagation and amplification of the inflam-
matory response. The accumulation of specific leukocytes at
the site of injury normally results in removal of the initiating
insult (e.g., phagocytosis of bacteria, immune complexes, ap-
optotic cells, cell debris, etc.) and tissue repair. Inactivation
and removal of inflammatory effector cells once their goal has
been accomplished are important to prevent chronic inflamma-
tion and progressive tissue destruction. Factors that govern the
termination of the inflammatory response are thought to in-
volve the downregulation of chemokine synthesis by local
factors (e.g., prostaglandins, TGF-␤) or a specific combination
of inflammatory mediators leading to local apoptosis of the
leukocytes involved (84).
During renal diseases, the infiltration of monocytes/macro-
phages and T cells into kidneys is thought to play a central role
in progressive interstitial fibrosis and the progression of
chronic renal failure (85). During this process, a cross-talk
between cytokines, vasoactive substances, chemokines, and
their respective target cells takes place. This interaction con-
tributes to the outcome, i.e., healing or progression of the renal
disorder. Chemokines appear to be integral players in this
complex and dynamic process.
Transgenic and Knockout Mice: Models of Chemokine
and Chemokine Receptor Action
The targeted disruption of chemokine and chemokine recep-
tor genes as well as the expression of chemokines as transgenes
has identified important roles for these molecules in specific
aspects of the inflammatory response.
The ability of chemokines to direct leukocyte infiltration
depends on a low regional expression level. In studies with
MCP-1 transgenic mice, the systemic overexpression of a
mouse mammary tumor virus long terminal repeat-MCP-1
J Am Soc Nephrol 11: 152–176, 2000
transgene led to a general paralysis of the response to this
chemokine (86). Only the local production as seen in insulin
promoter-MCP-1 transgenic mice was shown to be effective in
selectively recruiting monocytes (86). Besides persistent
MCP-1 expression and insulitis, the macrophage infiltrate did
not result in progressive tissue destruction. Therefore, addi-
tional costimulatory signals are required for the activation of
macrophages.
Knockout mice with a targeted disruption for either MCP-1
or the MCP-1 receptor CCR2 gene show a reduced capacity to
recruit monocytes and have suggested a fundamental role for
these molecules in the generation of atherosclerotic lesions
(87– 89). In addition, CCR2(⫺/⫺) mice show significant de-
fects in delayed-type hypersensitivity responses and in the
production of Th1-type cytokines (89). Mice deficient for
CCR5 show an increased humoral response to T cell-dependent
antigenic challenge, suggesting a novel role for CCR5 in
downmodulating T cell-dependent immune responses (90).
Targeted disruption of the eotaxin gene demonstrated that
eotaxin enhances the magnitude of early but not late eosinophil
recruitment after antigen challenge (91). CXCR4 is broadly
expressed by cells of the immune and central nervous system
and mediates the migration of resting leukocytes and hemato-
poietic progenitors in response to its ligand SDF-1 (92). Es-
sentially identical lethal defects were seen in mice deficient for
either CXCR4 or SDF-1 (93–95). These include severely re-
duced B lymphopoiesis, reduced myelopoiesis in bone marrow,
defective formation of the large vessels supplying the gastro-
intestinal tract, as well as cardiac defects and abnormal cere-
bellar development (93–95). In normal mice, CXCR5 is ex-
pressed on mature B cells and a subpopulation of T helper
cells. CXCR5 knockout mice lack inguinal lymph nodes and
possessed little or no normal Peyer’s patches. Lymphocyte
migration into splenic follicles of these mice were significantly
impaired (96). Information obtained with chemokine and che-
mokine receptor knockout in models of renal diseases is dis-
cussed in later sections.
Chemokines, Chemokine Receptors, and Viral Biology
Given the important roles of chemokines in diverse immune
processes, it is not surprising that viruses have exploited che-
mokine biology through the course of evolution. This phenom-
enon is emphasized by the large number of chemokine recep-
tors, chemokines, and general inhibitors or modulators of
chemokine action that are encoded by different viral genomes
(21,60,97–101).
One of the most dramatic developments in the viral/chemo-
kine connection is the observation that select chemokine re-
ceptors act as coreceptors for HIV entry into target cells
(16 –20). The chemokine ligands for these receptors can sup-
press infection by some strains of HIV-1 and may act as
important moderators of HIV replication in vivo (21). CCR5
represents the major coreceptor for macrophage-tropic strains
of HIV-1, whereas CXCR4 acts as a coreceptor for T cell-
tropic strains. CCR5 appears to play a unique role in viral
pathogenesis, as individuals homozygous for a nonfunctional
allele of CCR5 (CCR5⌬32) are highly protected from HIV-1
J Am Soc Nephrol 11: 152–176, 2000
infection (21). These results have opened new avenues of
research into the pathogenesis of HIV and have led to the
development of new strategies to block viral fusion.
Chemokines, Chemokine Receptors, and the
Kidney
All Types of Renal Cells Can Express Chemokines
upon Stimulation
Nearly 10 years ago, we and others described the induced
expression of chemokines by mesangial cells (Tables 4 and 5).
An expanding body of data now strongly suggests that chemo-
kines contribute to inflammatory glomerular as well as tubu-
lointerstitial diseases (2,53,54,102–110). All types of renal
cells (i.e., endothelial, mesangial, tubular epithelial, interstitial
cells, and podocytes) are able to produce chemokines in a cell-
and stimulus-specific manner. Details of the in vitro regulation
of various chemokines can be found in Tables 4 and 5 and in
several recent reviews (2,3). In general, proinflammatory stim-
uli such as TNF-␣, IL-1␤, IFN-␥, and lipopolysaccharide
(LPS), especially when used in combination, rapidly (within a
few hours) induce MCP-1, IL-8, and IP-10 (53,104,111–113).
The induction of RANTES occurs in a more delayed manner
(12 to 48 h). IgG and IgA immune complexes can also induce
upregulation of MCP-1, RANTES, IL-8, and IP-10 expression
by mesangial cells (Tables 4 and 5). Reactive oxygen species
are able to upregulate chemokine expression and may represent
a common mechanism of injury-induced chemokine generation
(106).
Growth factors such as platelet-derived growth factor and
basic fibroblast growth factor can induce MCP-1 and RANTES
expression by mesangial cells (114,115). This expression may
be related to the macrophage influx seen during proliferative
responses related to tissue repair, regeneration, and remodeling
(114). MCP-1 expression by proximal tubular cells is seen after
exposure to hyaluronan, a glucosaminoglycan degradation
product of extracellular matrix that accumulates in the inter-
stitium during kidney diseases (116). The interaction of CD40
with its ligand (CD154), together with IL-4 and IL-13, results
in MCP-1, RANTES, and IL-8 generation by cultured proximal
tubular cells (117), observations that may be relevant for
tubulointerstitial inflammatory cell infiltrates in transplant re-
jection and other forms of interstitial diseases.
The generation of chemokines by proximal tubular cells can
be induced by albumin, which is thought to mimic the effects
of proteinuria and may be related to the tubulointerstitial dam-
age seen in glomerular disease (118 –120). Wang et al. de-
scribed an increase of MCP-1 mRNA expression in proximal
tubular cells in response to delipidated bovine serum albumin
(BSA), holotransferrin, and apotransferrin, which was medi-
ated by NF-␬B (118,120). Lysine, an inhibitor of protein
uptake, reduced the MCP-1 expression (118). Zoja et al. found
a dose-dependent increase of RANTES expression by proximal
tubular epithelial cells exposed to BSA (119). However, this
effect required very high albumin concentrations (i.e., 10 to 30
mg/ml), probably not achieved in proximal tubular fluids.
Although the significance of these in vitro effects of albumin
Chemokines, Chemokine Receptors, and Renal Disease 159
on tubular epithelial cell chemokine production for the ne-
phrotic syndrome remains hypothetical, it does suggest that the
prolonged proteinuria and proximal tubular epithelial overload
of proteins (“nephrosis”) may lead to tubular cell activation
and chemokine induction. Furthermore, the role of lipids in the
nephrotic syndrome and of lipid droplets in proximal tubules
deserves attention in this context, as lipid oxidation may occur
and oxidized lipids can stimulate chemokine production (121).
Vasoactive Agents Can Stimulate Chemokine
Expression
Vasoactive agents and chemokines may directly interact.
Wolf et al. found that angiotensin II via the AT2 receptor could
stimulate RANTES production by glomerular endothelial cells
(122). Moreover, the infusion of angiotensin II into rats led to
an influx of macrophages into the glomerulus, which was
attenuated by the administration of an AT2 receptor antagonist
(122). The differential regulation of RANTES and MCP-1
could explain the apparent divergent reports from other groups
implicating the AT1 rather than the AT2 receptor in “chemo-
kine” stimulation (122–125).
The Production of Proinflammatory Chemokines Is
Transitory
Some chemokines appear to be constitutively expressed (i.e.,
those that control normal leukocyte trafficking). The proin-
flammatory chemokines appear to be kept under tight regula-
tory control and are expressed only in response to specific
stimuli (Tables 4 and 5). The basal expression of chemokines
often seen in cultured renal cells may represent a tissue-culture
artifact, as serum and endotoxin (a common contaminant of
growth media) are potent stimuli for chemokine induction
(112).
It is thought that the expression of proinflammatory chemo-
kines normally follows a self-limited course. Interestingly,
different time frames for the expression of various chemokines
in response to the same stimulus have been reported (112,126).
In general, chemokines that are rapidly induced (e.g., MCP-1)
return to “baseline” within a day. Stimulation with a combi-
nation of cytokines (e.g., TNF-␣, IL-1␤, and IFN-␥) often
results in a more prolonged expression (114,115). RANTES
expression can be slower with an increase seen after 12 to 24 h,
but the levels may remain elevated for days (114). The differ-
ent time courses suggest different signal transduction events
used for the individual chemokines.
Inhibition of Chemokine Expression
The expression of inflammatory chemokine genes can be
inhibited by glucocorticoids (127,128), cytokines such as
TGF-␤ (129), and prostaglandins (e.g., PGE2) (53). The inhib-
itory effect of prostaglandin appears to involve modulation of
the second messenger cAMP (51–53,130). Because TGF-␤ and
prostaglandins are generated at sites of tissue injury, the net
effect on local chemokine generation may depend on the bal-
ance between proinflammatory and anti-inflammatory agents.
The dual character of TGF-␤ is again illustrated by the report
that this cytokine can inhibit MCP-1 expression by proximal
 160

Table 6. Expression of chemokines in animal models of kidney diseases

Model Chemokines, Chemokine Receptors Intervention

Nephrotoxic serum GN in mice a MCP-1 (125,138,139,141,142) MCP-1 antibody (139)

a RANTES (138,139,141) Met-RANTES (139)
a IP-10 (141,142) MCP-1 knockout (140)
N MIP-1␣ (139,142) CCR1 knockout (141)
a CCR1 (142) AT1a knockout (125)
a CCR2 (142)
a CCR5 (142)
Nephrotoxic serum GN in rats a MCP-1 (143,144,146–152,156,157,160,250) MCP-1 antibody (146,156,157)
a RANTES (145,150,151) MIP-1 antibody (148)
a MIP-1␣ (143,148,149,151) Lymphotactin antibody (43)
a MIP-1␤ (143,148,150,151) MIP-2 antibody (153)
Journal of the American Society of Nephrology

a MCP-3 (151) CINC antibody (148)

a CINC (148) CCR5 antibody (43) (154)
a MIP-2 (148,149,250) vMIP II (150)
a TCA3 (151) PDTC (147)
a PF4 (149) CD8⫹ T depletion (143)
a IP-10 (149) Dexamethasone (149)
a Lymphotactin (155) Irradiation (144,148)
a Fractalkine (154) PMN depletion (148)
a CX3CR1 (154) Complement depletion (148)
a CCR2 (154) COX inhibitors (145)
a CCR5 (154) LPS (250)
IL-6 receptor antagonist (250)
IL-1 receptor antagonist (250)
Soluble IL-1 receptor (250)
Soluble TNF receptor (250)
Anti-Thy-1 nephritis in rats a MCP-1 (107,123,145,159–162) MCP-1 antibody (160)
a RANTES (145,162) AOP-RANTES (162)
AT1 receptor antagonists (123)
Complement depletion (107)
PGE infusion (161)
COX inhibitors (145)
Lupus nephritis in NZB/W mice a MCP-1 (163,164) Cyclophosphamide (163)
Bindarit (164)
Glucocorticoids (164)
Lupus nephritis MRL-Faslpr mice a RANTES (165) RANTES transfer (165)
J Am Soc Nephrol 11: 152–176, 2000
 Puromycin aminonucleoside nephrosis a MCP-1 (169–171, 251) MCP-1 antibody (169,251)
a MCP-3 (171) HMG-CoA reductase inhibitor (170)
N RANTES (169, 171)
N MIP-1␣ (169,171)
N MIP-1␤ (171)
a IP-10 (169)
J Am Soc Nephrol 11: 152–176, 2000

a TCA3 (171)
N MIP-2 (169)
a CINC (169)
Immune complex GN in rabbits a IL-8 (166,252) IL-8 antibody (166,252)
Immune complex GN in rats a MCP-1 (167) ACE inhibitor (167)
BSA injection in rats a MCP-1 (175)
High molecular weight dextran injection a RANTES (176)
in rats
Unilateral ureteral obstruction in rats a MCP-1 (178,179) ACE inhibitor (178)
AT1 antagonist (178)
LPS injection in rats a RANTES (177) L-arginine (177)
NO synthase inhibitor (177)
Adriamycin nephrosis in rats a IP-10 (233)
5/6 nephrectomized rats a MCP-1 (253) Protein diet (253)
AT II injection in rats a RANTES (122) AT2 antagonist (122)
Renal ischemia in rats a MCP-1/JE (180,182,183,254) Glucocorticoids (128)
a RANTES (182,183,254) Bioflavonoids (183)
a IL-8 (181) CD28-B7 blockade (182)
a KC/GRO␣ (180) ␣-MSH (181)
Lazaroid U-74389G (254)
Tubulointerstitial nephritis in rats a MCP-1 (173,174) MCP-1 antibody (174)
a MIP-1␣ (174) MCP-1 receptor antagonist (174)
a MIP-1␤ (174)
a CINC (255)
a MIP-2 (255)
a CCR2 (174)
a
GN, glomerulonephritis; vMIP, macrophage inflammatory protein of viral origin; PMN, polymorphonuclear neutrophil; COX, cyclo-oxygenase; NZB/W, New Zealand black/white
mice; AOP-RANTES, AOP-RANTES, a partially “blocking” RANTES derivative; HMG-CoA, hydroxymethylglutaryl CoA; ACE, angiotensin-converting enzyme; BSA, bovine serum
albumin; NO, nitric oxide; ␣-MSH, ␣-melanocyte-stimulating hormone. Other abbreviations as in Tables 1, 2, 4, and 5.
Chemokines, Chemokine Receptors, and Renal Disease
161
162 Journal of the American Society of Nephrology
tubular cells and at the same time enhanced synthesis of the
neutrophil-specific chemokine IL-8 (129).
Renal Cells May Also be Targets for Chemokines
Renal cells also express chemokine receptors. Thymus-de-
rived chemotactic agent-4 (TCA4), a mouse chemokine, can
bind to mouse mesangial cells and mediate chemotaxis and
proliferation (131). The TCA4-specific receptor expressed by
mesangial cells has not yet been identified (131,132). In a
human mesangial cell line, stimulation with IFN-␥ led to
induction of functional CCR1 expression (112). The activated
mesangial cells were found to migrate in response to RANTES
(112). In these experiments, no expression of CCR3, CCR4,
CCR5, and CCR8 could be detected (112).
Romagnani et al. demonstrated the expression of CXCR3
both in cultured human mesangial cells and renal biopsies (35).
The mesangial cells were shown to flux Ca2⫹, migrate in
response to IP-10, and proliferate in response to MIG (35). The
overall function of chemokine receptor expression by intrinsic
renal cells remains to be defined, but could play a role in
mesangial cell migration-proliferation during mesangial repair
and could even function as local immune modulator. It is
hoped that these questions can be addressed with receptor
knockout models.
Expression of Chemokines and Chemokine
Receptors in Experimental Models of Renal
Diseases
Animal models have been helpful in identifying potential
roles for chemokines in the initiation and propagation of renal
disease. The results of these experiments are sometimes diffi-
cult to interpret due to differences in the genetic backgrounds
of the animals used. The genetic background can profoundly
influence the susceptibility, type of inflammatory infiltrate, and
the eventual course of renal disease (133). The importance of
adequate backcrossing cannot be overstated because a signifi-
cant part of experimental findings assigned to the knockout
phenotype are often explainable by the different genetic back-
grounds used (134,135). The genetic background may also be
important because of polymorphisms in the chemokine gene
that may influence the expression of the chemokine (136,137).
Nephrotoxic Serum Nephritis
Many groups have used the classic model of nephrotoxic
serum nephritis (NTS-GN) induced by the injection of anti-
bodies against glomerular basement membranes for the study
of chemokine expression and action (138 –141). Mice with
accelerated NTS-GN show increased expression of RANTES
(138,139,141,142), MCP-1 (138 –142), IP-10 (141,142), and
MCP-3 (140) mRNA, whereas no change was seen in macro-
phage inflammatory protein-1␣ (MIP-1␣) expression (139).
The biologic action of different chemokines has been studied
through the use of neutralizing antibodies and specific chemo-
kine antagonists. Lloyd et al. blocked RANTES-associated
events in NTS-GN in CD1 mice (an outbred mouse strain) by
the use of the antagonist Met-RANTES. Animals treated with
J Am Soc Nephrol 11: 152–176, 2000
Met-RANTES showed reduced proteinuria, reduced T cell
infiltration, and mononuclear cell infiltration. However, glo-
merular crescent formation was not significantly reduced.
Treatment with a neutralizing MCP-1 antibody led to a reduc-
tion in proteinuria, infiltrating macrophages, and a striking
decrease in crescent formation and collagen production, sug-
gesting that MCP-1, and not RANTES, is involved in crescent
formation and early interstitial fibrosis (139). This issue was
also examined in MCP-1 knockout mice. Tesch et al. induced
NTS-GN in F1 generation littermates of MCP-1 knockout
129SV/J and wild-type C57BL/6 (i.e., a mixed genetic back-
ground). The animals developed a glomerular injury consisting
of hyalinosis, capillary dilation and thickening, focal segmental
sclerosis, and crescents (140). Glomerular hypertrophy or hy-
percellularity was not present (140). The lack of glomerular
chemokine expression in this model is consistent with the lack
of glomerular leukocyte infiltration, while the predominant
tubular MCP-1 expression was associated with tubulointersti-
tial cell infiltrate (140). In the MCP-1-deficient F1 generation
(129SV/JXC57BL/6), a reduced macrophage infiltrate adjacent
to tubules was seen. The authors suggest that tubular epithelial
cells represent the primary source of MCP-1 protein in this
model. MCP-1 so positioned could act to recruit peritubular
macrophages that could then promote tubular interstitial injury
(140). Hisada et al. used the NTS-GN model in mice to
evaluate the role of angiotensin II type 1a receptor (AT1a) by
use of AT1a receptor-deficient mice (AT1a(⫺/⫺)) (125). AT1a-
deficient mice were backcrossed with C57BL/6 for five gen-
erations (representing adequate backcrossing) (125). In these
animals, a peak of MCP-1 mRNA expression was seen after
6 h. An additional increase in MCP-1 after 14 d, which was
stronger in the AT1a(⫹/⫹) than in the AT1a(⫺/⫺) mice, was
also seen (125). The higher expression of MCP-1 in wild-type
mice was associated with a more severe disease course (125).
The authors propose that angiotensin II via the AT1a receptor
mediates the late MCP-1 expression and may play a role in
progression of immune-mediated renal injury.
NTS-GN results in induction of CCR1, CCR2, and CCR5
that is associated with the expression of corresponding chemo-
kine mRNA for MCP-1, RANTES in CD1 mice (142). Another
recent abstract indicates that mice deficient in CCR1 show
more severe renal impairment and proteinuria than the wild-
type mice, suggesting a novel immune modulatory role for
CCR1 (141).
In Wistar-Kyoto rats, the injection of NTS-GN antibodies leads
to crescentic glomerulonephritis in which CD8⫹ T cells are
thought to play a major role (143). In this model, an upregulation
of MCP-1 (143–152), MIP-1␣ (143,148,149,151), MIP-1␤
(143,148,151), RANTES (145,150,151), MCP-3 (151), CINC
(148,149), MIP-2 (148,149,153), PF4 (149), TCA3 (151), fracta-
lkine (154), lymphotactin (155), and IP-10 mRNA (149) was
detected (Table 6).
A correlation between the expression of neutrophil-attract-
ing chemokines and an early neutrophil influx and the later
expression of macrophage-attracting chemokines followed by a
macrophage influx was described (148,149). The MCP-1
mRNA was localized to intrinsic glomerular cells after 3 h.
J Am Soc Nephrol 11: 152–176, 2000
After 24 h, the predominant source of MCP-1 was from infil-
trating monocytes/macrophages (156). MCP-1 protein (156)
was demonstrated in glomeruli (144,150,152,157), vascular
endothelial cells (157), and tubular epithelial cells (157). Ex-
pression of RANTES (150), MIP-1␣ (148), MIP-1␤ (150), and
MIP-2 (153) protein was also demonstrated. Recently, the
upregulation of fractalkine mRNA, as well as an induction of
the fractalkine receptor (CX3CR1) mRNA, was described in
NTS-GN. Fractalkine protein was localized to glomerular en-
dothelium (154). Antibodies against CX3CR1 markedly atten-
uated the crescentic nephritis (154). A neutralizing antibody
against MCP-1 decreased macrophage infiltration of the glo-
meruli and reduced proteinuria (146,156,157). This beneficial
effect was shown to persist to day 56 after induction of the
disease, with lower proteinuria and blood urea nitrogen seen
compared with untreated rats (157).
Neutralizing antibodies against other chemokines have also
shown partial “positive” effects. Blocking MIP-1␣ and
MIP-1␤ resulted in a 60% reduction in proteinuria after 24 h,
but the animals did not show a corresponding reduction in
leukocyte influx (148). Blocking CINC (the rat homologue of
GRO) also resulted in decreased proteinuria and reduced early
glomerular cell infiltration by polymorphonuclear neutrophils
(148). The combination of anti-CINC and anti-MIP treatment
did not show an additive beneficial effect (148). A single
injection of an anti-MIP-2 (CXC chemokine) antibody resulted
in a reduced neutrophil influx and a significant decrease in
proteinuria (153).
A natural and broadly acting chemokine receptor antagonist
of viral origin, vMIP-II, can block both CC and CXC receptors
(99,150). Treatment with vMIP-II decreased infiltration with
CD8⫹ T cells, macrophages and reduced proteinuria to one-
third of the control group (150).
Agents that modulate expression of chemokines have bene-
ficial effects on the outcome of the disease. Treatment with
dexamethasone can limit glomerular MCP-1 expression, as
well as polymorphonuclear neutrophil and monocyte/macro-
phage infiltration (149). MCP-1 mRNA expression is con-
trolled to a significant extent by the transcription factor NF-␬B
(147). Treatment of rats with the NF-␬B inhibitor pyrrolidine
dithiocarbamate led to a decrease in MCP-1 expression, re-
duced proteinuria, and preserved renal function (147). Treat-
ment of animals with a nonselective cyclo-oxygenase (COX)
inhibitor (indomethacin) or selective COX-2 inhibitors
(meloxicam, SC 58125) resulted in an upregulation of MCP-1
and RANTES (145). The nonselective COX inhibitor led to a
stronger induction of chemokines compared with the group
treated with the COX-2 inhibitor. COX products (i.e., prosta-
glandins) may serve as endogenous chemokine repressors
(Table 6) (53,145).
In summary, the animal models of nephrotoxic serum glo-
merulonephritis suggest a role for chemokines in the initiation
and propagation of this disease. The blockade of select che-
mokines, or their receptors, can lead to a partial improvement
of the disease. Surprisingly, recent abstracts indicate that in-
terference with lymphotactin (43), or the elimination of CCR1
Chemokines, Chemokine Receptors, and Renal Disease 163
(141), may worsen the disease, suggesting “anti-inflammatory”
functions for some chemokines.
Anti-Thy-1 Nephritis
In rats the injection of anti-thymocyte antiserum can lead to
complement-dependent mesangiolysis followed by monocyte
influx and a mesangial proliferative glomerulonephritis
(107,158). These lesions heal spontaneously over several
weeks. The type of renal disease is dependent on the rat strain
used. Wistar and Lewis rats develop a transient influx of
macrophages (159). By contrast, F344 rats do not show an
influx of macrophages, but have a pronounced proliferative
glomerulopathy (159).
MCP-1 (107,123,145,160 –162) and RANTES (145,162) are
upregulated in this model, and MCP-1 protein localizes to
glomeruli (107,159). An important role for MCP-1 in this
disease process was suggested in blocking experiments using
MCP-1 neutralizing antibodies, which led to a decreased infil-
tration of monocytes/macrophages after 24 h (160). Treatment
with AOP-RANTES (a partially “blocking” RANTES deriva-
tive) as described in a recent abstract showed a 60% decrease
of glomerular macrophage infiltration and ameliorated colla-
gen type IV deposition (Table 6) (162).
Prostaglandin E (PGE) infusion (161), depletion of comple-
ment (107), and AT1 antagonists have been shown to signifi-
cantly decrease MCP-1 expression and glomerular macrophage
infiltration (123). As seen in the NTS-GN model, COX inhibitors
enhance production of MCP-1 and RANTES (Table 6) (145).
Models of Systemic Lupus Erythematosus
New Zealand black mice crossed with New Zealand white
(NZB/W) mice serve as a model for lupus nephritis. The F1
hybrid develops circulating antibodies to nucleic acid, renal
immune deposits, and proteinuria (163). MCP-1 mRNA ex-
pression is upregulated during the initial 6 mo of the disease
(163). In situ hybridization localized MCP-1 mRNA to intrin-
sic glomerular cells, infiltrating mononuclear cells, and tubular
epithelium (163). At later stages of the disease, MCP-1 expres-
sion in tubuli corresponded to an “adjacent” leukocyte infil-
tration (163). Mice treated with cyclophosphamide showed
better survival, lower proteinuria, as well as less severe glo-
merular and interstitial changes, and reduced MCP-1 expres-
sion (163). Bindarit, a novel immunosuppressive drug, was
recently tested in this model at different time points and in
combination with low-dose steroids (164). Starting at 2 mo of
age, bindarit administration significantly reduced expression of
MCP-1, proteinuria, renal impairment, and prolonged animal
survival (Table 6) (164).
The MRL-Faslpr mouse serves as an additional model of
systemic lupus. These animals show an upregulation of RAN-
TES and develop a nephritis with glomerular, perivascular, and
interstitial inflammation (165). Tubular epithelial cells, genet-
ically manipulated to express RANTES protein, were injected
into kidneys of MRL-Faslpr mice. This led to an interstitial
infiltrate composed mainly of CD4⫹ T cells and to a lesser
extent CD8⫹ T cells and macrophages. By contrast, when
colony-stimulating factor-1 (CSF-1) was overexpressed in kid-
164 Journal of the American Society of Nephrology
neys using the same approach, an equal number of CD4⫹ and
CD8⫹ T infiltrating cells were seen. The authors postulated
complementary roles for RANTES and CSF-1 during autoim-
mune nephritis in MRL-Faslpr mice.
Immune Complex Glomerulonephritis
A model of immune complex glomerulonephritis in the
rabbit is induced by the administration of BSA in combination
with LPS (166). An influx of neutrophils into glomeruli, fusion
of foot processes, and proteinuria by day 8 characterize this
model (166). IL-8 expression by affected glomeruli was asso-
ciated with an increased urinary IL-8 excretion (166). Injection
of an anti-IL-8 antibody reduced glomerular neutrophil infil-
tration, prevented fusion of foot processes, and normalized
proteinuria (166).
In Wistar rats, an immune complex nephritis was induced by
the injection of ovalbumin over a period of several weeks. This
resulted in an increase of MCP-1 mRNA expression in the renal
cortex (167). Immunohistochemistry showed intense MCP-1
staining in glomerular capillaries, mesangial areas, proximal tu-
bular epithelium, and interstitial mononuclear infiltrates (167).
Treatment with an angiotensin-converting enzyme inhibitor re-
duced MCP-1 expression (167). These data suggest a possible link
between renal immune injury, the angiotensin system, and spe-
cific chemokines (Table 6) (122,123,125,167).
A recent abstract described increased MCP-1, RANTES,
CCR1, CCR2, and CCR5 mRNA during the early phase of
apoferritin-induced immune complex nephritis in Balb/c mice
(168). This upregulation of chemokines preceded the glomer-
ular infiltration of leukocytes. Chemokine expression and the
leukocyte infiltration disappeared after discontinuation of an-
tigen exposure and the initiation of healing (168).
Puromycin Aminonucleoside Nephrosis
In rats the injection of puromycin aminonucleoside leads to
proteinuria. A marked mononuclear interstitial infiltrate (pre-
dominantly macrophages) occurs together with an increase of
IP-10, MCP-1, MCP-3, and TCA3 mRNA expression (169 –
171). Expression of CINC, MIP-2, and MIP-1␣ was not de-
tected, and RANTES expression was low and did not change
(171). A neutralizing MCP-1 antibody reduced interstitial in-
filtration by macrophages (169).
The hepatic hydroxymethylglutaryl CoA reductase inhibitor
lovastatin suppressed MCP-1 expression by mesangial cells
(172) and significantly reduced the interstitial influx of mac-
rophages in the puromycin model (170). These findings are of
particular interest, because interstitial infiltrates are a prognos-
tic factor for the progression of human disease (85).
Tubulointerstitial Nephritis
Immunization of Brown Norway rats with bovine tubular
basement membrane induces a severe tubular interstitial ne-
phritis (173). In this model, MCP-1 mRNA expression pre-
cedes an influx of mononuclear cells on day 8 but is no longer
detectable by day 10 (173). The early increase in CINC and
MIP-2 mRNA expression was associated with neutrophil in-
filtration. A later expression of MCP-1, MIP-1␣, and MIP-1␤
J Am Soc Nephrol 11: 152–176, 2000
mRNA correlated with a monocyte influx (174). Treatment
with a neutralizing MCP-1 antibody or an MCP-1 receptor
antagonist reduced macrophage influx (20 and 60%, respec-
tively) (Table 6) (174).
Other Renal Disease Models
Interstitial infiltrate and fibrosis in rats can be induced by
daily injections of BSA. In a study by Eddy and Giachelli,
Lewis rats received intraperitoneal injections of BSA after
nephrectomy of the left kidney (175). MCP-1 mRNA expres-
sion was significantly elevated after 2 and 3 wk in whole
kidney preparations (175). MCP-1 protein was found in glo-
meruli and occasionally in tubular cells (175). Because a
significant macrophage infiltrate is seen in this model before
MCP-1 expression, the infiltrate appears to be due to additional
chemoattractants (175).
Injection of diethylaminoethyl dextran leads to proteinuria in
Lewis rats but without significant cellular infiltration and with-
out immune complex deposition (176). In this model, strong
glomerular localization of RANTES was seen, but apparently
was insufficient to cause a cell infiltrate (176).
A model of endotoxemia by LPS injection in Wistar rats
leads to glomerular RANTES expression and an influx of
macrophages (177). Supplementation with L-arginine, a pre-
cursor for nitric oxide (NO) synthesis, reduced the RANTES
expression. A nonspecific NO synthase inhibitor resulted in
increased RANTES expression and a glomerular infiltrate
(177). These studies suggest that the NO pathway may be a
counter regulator for LPS-induced RANTES expression and
macrophage infiltration.
Chemokine Expression in Unilateral Ureteral
Obstruction
Interstitial macrophage infiltration is a prominent feature of
unilateral ureteral obstruction (178). MCP-1 mRNA is induced
by tubular cells in the obstructed kidney (178,179). Angioten-
sin-converting enzyme inhibition and an AT1 antagonist de-
creased MCP-1 expression and reduced the macrophage infil-
trate and fibrosis (178).
Chemokine Expression in Renal Ischemia
As early as 1991, Safirstein et al. described the expression of
mRNA of the “early response genes” JE (MCP-1) and KC
(GRO-␣) during renal ischemia (180). The induction of MCP-
1/JE can be prevented by treatment with methylprednisolone
(128). Furthermore, renal ischemia causes an upregulation of
IL-8 that can be inhibited by treatment with ␣-melanocyte-
stimulating hormone, raising the possibility that ␣-melanocyte-
stimulating hormone may act as a counter-regulatory hormone
for chemokine induction (181).
Temporary renal pedicle occlusion with simultaneous right
nephrectomy resulted in expression of RANTES and MCP-1
after 2 d (182,183). Treatment with bioflavonoids, agents with
potential immunosuppressive and renoprotective properties,
preserved histologic integrity and renal function, and prevented
MCP-1 and RANTES upregulation (183). Blocking the T cell
costimulatory molecule B7 by a soluble CTLA4Ig protein
J Am Soc Nephrol 11: 152–176, 2000
resulted in nearly complete suppression of RANTES and
MCP-1 (182). Thus, non-immune-mediated injuries can be
potent inductors of chemokines, which appear to play an inte-
gral role in tissue injury and repair and the associated leukocyte
influx, regardless of the initiating insult.
Renal Transplantation
Rat models of transplantation have allowed a functional
analysis of the role of chemokines in acute and chronic renal
rejection (81,184,185). In acute renal transplant rejection in the
rat, Nagano et al. found that RANTES mRNA was upregulated
by 6 h during the initial transplant rejection phase and again
after 3 to 6 d (185). The authors speculated that expression of
E-selectin and RANTES within the first few hours after en-
graftment may occur secondary to ischemic injury and could
help trigger subsequent immunologic events (185). In addition,
they concluded that macrophages and their products may play
a larger role in the process than previously appreciated (185).
The functional role of RANTES and its receptors was re-
cently evaluated in rat models of acute renal allograft rejection
using the RANTES receptor antagonist Met-RANTES (81).
Treatment with Met-RANTES significantly reduced the vas-
cular and tubular damage associated with acute rejection and
suppressed mononuclear infiltration (81). Treatment with Met-
RANTES and low-dose cyclosporin A markedly attenuated the
damage to vessels, tubules, and the interstitial rejection (81).
The potential clinical advantage of chemokine antagonists such
as Met-RANTES may lie in their early effects on the suppres-
sion of cellular infiltration and subsequent graft damage, which
may help lower the inclination toward the development of
chronic transplant dysfunction.
Chemokines in Human Kidney Diseases
Much has been learned about the relationships between
chemokine expression and the progression of human renal
disorders. Obviously, biopsy studies can provide only a snap-
shot of a given stage in the development of a disease. Recent
developments suggest that monitoring chemokines in the urine
may provide a more dynamic picture of the inflammatory state
of the kidney (186 –192).
Chemokines and Chemokine Receptors in Glomerular
Diseases
The expression of IL-8 and MCP-1 (108,186,188,193) has
been reported In IgA nephropathy. IL-8 mRNA was localized to
glomeruli (188), and MCP-1 protein was detected in vascular
endothelial cells (188), tubular epithelial cells (108,186,188,193),
infiltrating mononuclear cells (186,188), and parietal cells of
Bowman’s capsule (186). MCP-1 was not seen in glomeruli that
did not show proliferative nephropathy (144,194). In mild disease
courses, MCP-1 was rarely expressed, whereas severe cases with
interstitial infiltrates showed strong expression of MCP-1, which
correlated well with monocyte infiltration and interstitial damage
(186). Renal function was found to be significantly worse in
patients with detectable MCP-1 expression (194). In IgA nephrop-
athy, CCR1, CCR2a, and CCR2b were detected in biopsy tissue
by reverse transcription-PCR (194). A strong glomerular expres-
Chemokines, Chemokine Receptors, and Renal Disease 165
sion of CXCR3, primarily by mesangial cells, was found by
immunohistochemistry (35). CXCR3 was also found on infiltrat-
ing leukocytes, and endothelial and vascular smooth muscle cells
(35). On the other hand, CCR5-positive cells are not present in
glomeruli, but were a prominent part of the interstitial infiltrate
(195). In summary, in IgA nephropathy MCP-1 is expressed by
tubulointerstitial cells, and the chemokine receptors CCR2 and
CCR5 are found on inflammatory cells. CXCR3 is expressed on
intrinsic glomerular cells and may act as a mechanism for glo-
merular mesangial proliferation (35).
MCP-1 expression has not been found in glomeruli from
nonproliferating diseases, such as membranous nephropathy,
minimal change disease, thin basement membrane disease, and
diabetic nephropathy (144). In contrast to the absence of glo-
merular chemokine expression in membranous nephropathy,
MCP-1 and RANTES were expressed by tubular epithelial
cells during proteinuria, and their expression was associated
with interstitial cell infiltration and fibrosis (193,196). No
CCR5-positive cells were detected within glomeruli during
membranous nephropathy, but CCR5-positive mononuclear
cells—predominantly CD3-positive T cells—were seen in the
interstitium (195). This CCR5-positive T cell infiltrate may be
related to the tubulointerstitial damage noted in these biopsies
(195).
Chemokines and Chemokine Receptors in Proliferative
and Crescentic Glomerulonephritis
Rovin et al. described the distribution of MCP-1 by immu-
nohistochemistry in patients with idiopathic crescentic glomer-
ulonephritis, Wegener’s granulomatosis, and lupus nephritis
(144). A focal, granular staining for MCP-1 with a mesangial
distribution (and in some crescents) was detected (144). Cock-
well et al. studied 20 patients with glomerulonephritis due to
different forms of vasculitis by in situ hybridization (197).
MCP-1, MIP-1␣, and MIP-1␤ were expressed in some glomer-
uli at similar levels and in crescents (197). RANTES expres-
sion was described in 11% of the glomeruli (197). MCP-1 was
not detected in the glomeruli of patients with lupus nephritis
(189). By in situ hybridization, patients with lupus nephritis
showed MCP-1 expression on endothelial cells, cortical tu-
bules, and infiltrating mononuclear cells in the interstitium
(189,197). In patients with cryoglobulinemic glomerulonephri-
tis, a significant upregulation of MCP-1 expression was seen in
glomeruli and in areas of tubulointerstitial damage (191). The
MCP-1 was localized to tubular cells, parietal cells, and cells of
the glomerular tuft, and correlated with glomerular and inter-
stitial macrophage infiltration (191). The expression of
MIP-1␤ and MIP-1␣ fits with the preliminary observation that
crescents contain CCR5-positive cells (198). In crescentic glo-
merulonephritis, the expression of MIP-1␣ and MCP-1 was
found in tubules, peritubular capillaries, and infiltrating leuko-
cytes. MIP-1␣ was also present in crescents (199). Cockwell et
al. described the distribution of IL-8 mRNA and protein in
patients with antineutrophil cytoplasmic antibody-associated
glomerulonephritis (200). About 30% of the glomeruli showed
IL-8 expression at sites of inflammation. Outside the glomer-
uli, IL-8 mRNA was detected in interstitial infiltrates and
166 Journal of the American Society of Nephrology
proximal tubular epithelial cells. IL-8 protein was present in
50% of the glomeruli and was prominent in crescents and
parietal cells. Intraglomerular leukocyte accumulation corre-
lated with the IL-8 expression (200).
Chemokines and Chemokine Receptors in
Tubulointerstitial Diseases
Biopsy samples from patients with acute interstitial nephritis
were studied by in situ hybridization and immunohistochem-
istry for MCP-1 expression (186). MCP-1 was expressed by
tubular as well as infiltrating cells and was detected in parietal
cells of Bowman’s capsule but not within the glomerular tuft.
Eitner et al. described expression of CCR5 mRNA in intersti-
tial infiltrates (201) that was confirmed by immunohistochem-
istry, where CCR5-positive cells correlated with the presence
of an interstitial T cell infiltrate (195).
Chemokines and Chemokine Receptors during Renal
Transplant Rejection
Acute allograft rejection is characterized by a mononuclear
cell infiltrate consisting primarily of T cells, macrophages, and
occasional eosinophils (202,203). The chemokines IL-8, ENA-
78, MCP-1, MIP-1␣, MIP-1␤, and RANTES have all been
implicated in the pathogenesis of acute rejection (204 –209).
One of the most studied chemokines in this regard is the CC
chemokine RANTES (205,210). During cell-mediated rejec-
tion, in situ hybridization localized RANTES mRNA to infil-
trating cells and tubular epithelium (210). RANTES protein
was found on mononuclear cells, tubular epithelium, and the
vascular endothelium (205). This expression mirrors the dis-
tribution of CCR5-positive leukocytes found in areas of endo-
thelialitis, tubulitis, and interstitial infiltrates during cellular
rejection (195). Strehlau and coworkers used reverse transcrip-
tion-PCR to evaluate gene expression in human renal allograft
biopsies and concluded that RANTES and IL-8 expression are
sensitive but not specific markers of allograft rejection (211).
Grandaliano et al. found an increased amount of MCP-1 in
urine during rejection corresponding to elevated renal MCP-1
expression (204). An increased amount of urinary IL-8 was
described during acute rejection, which returned to normal
levels after successful treatment (206).
DARC Expression in Kidney Disease
A study of children with HIV-associated nephropathy, HIV-
associated hemolytic uremic syndrome (HUS), and classic
HUS (212) reported DARC mRNA and protein localized to
endothelial cells of postcapillary renal venules in normal kid-
ney. The biopsies of the patients showed increased DARC
expression on glomerular capillaries, collecting duct epithelial
cells, and interstitial inflammatory cells (212). DARC upregu-
lation on peritubular endothelium was described during trans-
plant rejection especially at sites of inflammation in a recent
abstract (213). The role of this upregulation of DARC during
renal diseases is unknown.
J Am Soc Nephrol 11: 152–176, 2000
Quantification of Urinary Chemokines as a Measure of
Renal Production
Elevated urinary MCP-1 levels occur in proliferative lupus
nephritis, IgA nephropathy, proliferative glomerulonephritis
associated with endocarditis, membranoproliferative glomeru-
lonephritis, crescentic glomerulonephritis, and in transplant
rejection (187–191,199). Only moderately increased amounts
of MCP-1 have been measured in membranous nephropathy,
focal segmental glomerulosclerosis, and diabetic nephropathy,
consistent with moderate glomerular cell infiltration in these
diseases (190). Urinary MCP-1 levels correlated with urinary
protein excretion and macrophage infiltration of the glomeruli
(190). No correlation between serum and urine MCP-1 was
seen (187).
High urinary MCP-1 excretion was found in patients with
active lupus nephritis compared with healthy control subjects
(189,190,192). Urinary MCP-1 levels were reduced by high-
dose glucocorticoid therapy and remained low during remis-
sion (187,189,192). Elevated urinary excretion of MCP-1 and
MIP-1␣ was also reported in patients with crescentic glomer-
ulonephritis, and treatment reduced excretion of both chemo-
kines (199). Similar results were reported for IL-8, with high
levels seen during severe lupus nephritis, and a significant
reduction in IL-8 levels was seen after glucocorticoid therapy
(187,189).
A correlation between urinary MCP-1 levels, mesangial
proliferation, and interstitial infiltrate has been described in
IgA nephropathy (186,188). Patients with severe IgA nephrop-
athy showed higher MCP-1 levels compared with patients with
mild disease (186). IL-8 levels were only elevated during the
acute phase and correlated with glomerular endocapillary pro-
liferation and the degree of hematuria (188).
Other renal diseases that present elevated levels of IL-8
include acute postinfectious glomerulonephritis, membrano-
proliferative glomerulonephritis, and cryoglobulinemia (187).
The urinary IL-8 levels were higher in patients with glomerular
leukocyte infiltration than in those without infiltration (187).
Children with HUS showed a significant increase in both IL-8
and MCP-1 excretion (214). Thus, urinary excretion of che-
mokines may reflect the intrarenal inflammatory cell infiltrate
and may be of prognostic value as a measure of continued
intrarenal inflammation.
A Model for Chemokines in Renal Diseases
The emerging picture of chemokine action allows us to
construct models of potential roles for chemokines in various
pathophysiologic processes thought to contribute to renal dis-
orders. In this model (Figure 1A), a pathologic insult to the
glomerular or tubulointerstitial compartment activates intrinsic
renal cells and leads to the local generation of proinflammatory
mediators (initiation phase) (Figure 1B). This insult may be
immunologic, toxic, ischemic, or mechanical, and may target a
specific renal cell type (e.g., endothelial, mesangial, and epi-
thelial or interstitial cell). The expression of select chemokines
and chemokine receptors, together with the local release of
inflammatory mediators (such as IL-1, TNF-␣, IFN-␥, platelet-
activating factor, reactive oxygen species, etc.), promotes the
J Am Soc Nephrol 11: 152–176, 2000
Figure 1. Hypothetical model of the role of chemokines and chemokine receptors during progressive renal diseases. (A) Normal renal tissue.
(B) Initiation phase. (C) Amplification phase. (D) Progression phase.
upregulation and activation of selectins and integrins on leu-
kocytes and endothelial cells leading to adhesion, transendo-
thelial migration, and infiltration of specific subsets of leuko-
cytes. T cells, monocytes, and polymorphonuclear leukocytes
appear to preferentially adhere to different microvascular com-
partments in the kidney. For example, T cells are rare in
glomeruli but are common in interstitial infiltrates. The spe-
cialized endothelia found in the kidney, e.g., glomerular, peri-
tubular, have different characteristics, but at present informa-
tion on the surface expression of selectin ligands is lacking
(215). The role of this endothelial heterogeneity in the kidney
Chemokines, Chemokine Receptors, and Renal Disease 167
for the leukocyte adhesion and infiltration process remains to
be elucidated.
An additional consequence of local cell activation may in-
clude the induced expression of chemokine receptors such as
CCR1 and CXCR3 by mesangial cells, and other renal cell
types. The expression of CXCR3 by mesangial cells in concert
with local production of the chemokine IP-10 could lead to
mesangial cell proliferation (35).
During the “amplification phase,” spillover of proinflamma-
tory factors from affected glomeruli could reach the peritubular
capillary circulation, as well as the tubular lumen via ultrafil-
168 Journal of the American Society of Nephrology
tration, especially in the context of proteinuria with loss of the
ultrafiltration barrier. In addition, protein and lipids escaping
through damaged glomeruli could “stress” proximal tubular
cells. In concert with inflammatory mediators, this could lead
to an activation of tubular and interstitial cells and the produc-
tion of additional chemokines, resulting in interstitial mononu-
clear cell infiltration. Similarly, the parietal cells of Bowman’s
capsule apparent bystander cells in this process could become
activated and thus release chemokines into the surrounding
interstitium. This sort of event could help explain the accen-
tuated periglomerular infiltrate seen in some renal diseases.
The periglomerular infiltrate may play a role in the eventual
rupture of Bowman’s capsule, which would open the door for
T cells, macrophages, and fibroblasts to invade the urinary
space and damage the parietal and visceral epithelial cells. This
could be an example of the “point of no return,” in which
amplification of a glomerular injury results in irreversible
sclerosis. Thus, a cycle initiated through glomerular damage
could, in the absence of sufficient counter-regulatory signals,
result in downstream tubular-interstitial injury, interstitial in-
flammation, and fibrosis (progression phase) (Figure 1D).
Of course, renal inflammation does not always end with
chronic damage. The events initiated during inflammation nor-
mally end in resolution of the disease process. Recent results
suggest that some chemokines and their receptors may also
assist in downmodulating the inflammatory response, a hy-
pothesis that deserves further investigation.
Conclusions, Future Directions, and
Therapeutic Outlook
Current therapies used for the treatment of renal diseases can
influence chemokine expression. The production of chemo-
kines by various renal and infiltrating cells can be suppressed
by glucocorticoids in vitro (126,216). Glucocorticoids function
in part via an inhibition of transcription factor NF-␬B (217),
and blockade of NF-␬B function leads to suppression of che-
mokine release by renal cells (51,218). Elevated urinary che-
mokines in human lupus nephritis are decreased by glucocor-
ticoid therapy (187,189,190,192). Glucocorticoid suppression
of chemokine expression may be one component of the general
beneficial effects of glucocorticoid therapy seen in lupus ne-
phritis.
In animal models, a connection between angiotensin II,
chemokine production by renal cells (122), and beneficial
effects of angiotensin blockade were described (122,125,178).
Thus, a reduction in chemokine production may be one bene-
ficial effect of angiotensin-blocking drugs in the treatment of
renal disease.
The side effects of nonsteroidal anti-inflammatory drugs
(NSAID) are well established and are mostly related to alter-
ations in renal hemodynamics and transport (219). The rare
NSAID-related nephrotic syndrome and interstitial nephritis
are thought to result from immunologic effects of these drugs
(219). In this context, it is of interest that PGE suppresses
chemokine production in mesangial cells and chemokine re-
ceptor expression on monocytes-macrophages (53,220). There-
J Am Soc Nephrol 11: 152–176, 2000
fore, PGE and possibly PGI2 may also inhibit chemokine
production. This is supported by studies in the Thy 1.1 model,
in which PGE administration decreases MCP-1 generation and
cyclo-oxygenase inhibitors enhance MCP-1 and RANTES ex-
pression (145,161). In addition, PGE has been shown to de-
crease monocyte-macrophage infiltration (161), whereas
NSAID can enhance it (145). Thus, NSAID may enhance renal
chemokine production and hence renal inflammation, an addi-
tional reason for avoiding their use in patients with renal
disease.
Taken together, these studies shed light on therapeutic pro-
tocols that may influence the regulation of chemokine/chemo-
kine receptor expression and suggest efficacy for the develop-
ment of agents that selectively target chemokine biology. In
general, receptor-blocking drugs have proven to be very suc-
cessful therapeutically. The development of chemokine recep-
tor antagonists for the treatment of inflammatory disorders and
HIV is a major focus of the pharmaceutical industry. The
redundancy of the chemokines, which creates a robust system,
could be a drawback for therapeutic interventions (57). There-
fore, blockade of multiple chemokine receptors simultaneously
might be necessary. This strategy has already been successfully
exploited by nature, as viruses can produce broad-spectrum
chemokine antagonists, e.g., vMIP-II (150). On the other hand,
the redundancy might be of potential benefit for the treatment
with antagonists, as this might lead to a reduction of side
effects.
Given the large number of chemokines and chemokine re-
ceptors, the intricate control of their expression, and their
diverse biologic actions, the emerging story reveals a biologic
system that is extraordinarily complex. The therapeutic inter-
vention into the system might depend on the underlying dis-
ease, the time point, and comedication. Based on experimental
models and the immunohistologic findings in human biopsies,
blockade of CCR5-positive infiltrating cells might prove to be
a promising therapeutic strategy for inflammatory renal dis-
eases including transplant rejection. Clearly, antagonists for
chemokines and their receptors have the potential to become
additional therapeutic tools in inflammatory disorders, includ-
ing kidney diseases.
Acknowledgments
We thank Holger Maier for help with graphics. Our special thanks
go to Bruno Luckow, Bernhard Banas, Matthias Mack, and Joachim
Anders for carefully reading the manuscript.
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