Biology of glomerular podocytes

Author:
Pierre Ronco, MD, PhD
Section Editors:
Richard J Glassock, MD, MACP
Brad H Rovin, MD
Deputy Editor:
John P Forman, MD, MSc

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review
process is complete.
Literature review current through: Sep 2016. | This topic last updated: Jul 12,
2013.

INTRODUCTION — The healthy kidney filters metabolic byproducts into the urine but
prevents the passage of albumin and other larger essential molecules. This selective
filtration occurs across the glomerular capillary wall:

●Under normal circumstances, the glomerular capillary wall is extremely

permeable to water and small solutes, but negligibly to albumin or other proteins
of equivalent molecular weight or larger.
●Defects in the glomerular capillary wall result in increased permeability to
albumin and proteins of similar size or even larger, causing proteinuria.
●Electrical potential differences generated by transglomerular flow may modulate
the flux of anionic (charged) albumin across the glomerular capillary wall [1].

The traditional view that the glomerular capillary wall hinders the transit of protein is
largely based upon micropuncture studies that demonstrated very low concentrations
of albumin in Bowman's space in non-nephrotic animals [2,3]. This view has been
challenged by newer data that have demonstrated by intravital 2-photon microscopy,
much higher concentrations of albumin in Bowman's space than were reported
previously [4]. Given the novelty of the technique of intravital 2-photon microscopy,
these observations need to be validated in other systems and species, especially since
they substantially alter our understanding of the pathogenesis of proteinuria [5-7].

It is not known, however, why the filter does not routinely clog with large proteins that
enter the glomerular basement membrane (GBM). It has been hypothesized that
proteins cross the GBM mainly by diffusion rather than by liquid flow, whereas water
crosses entirely by flow [8]. An active transport that removes immunoglobulins that
accumulate at the filtration barrier has been identified [9]. This transport involves the
neonatal Fc receptor (FcRn). In a murine model, IgG accumulated in the GBM of FcRn-
deficient mice as they aged, and tracer studies showed delayed clearance of IgG from
the kidneys of FcRn-deficient mice [9]. Genetic or acquired impairment of the clearance
machinery may be a common mechanism promoting glomerular diseases.

Over the last decade, studies among patients with hereditary proteinuric syndromes
have markedly advanced our knowledge of the structure and composition of the
glomerular capillary wall and the changes in its composition that lead to proteinuria.
However, the changes in the glomerular capillary wall that underlie proteinuria in
hereditary diseases do not necessarily account for the proteinuria that accompanies
acquired causes of nephrotic syndrome, which are much more common. Thus, the
underlying molecular mechanisms of acquired proteinuric diseases remain less well
characterized.

It is increasingly appreciated that defects in podocyte structure and function result in

increased glomerular permeability. This topic review will focus primarily on the biology
of glomerular podocytes and defects in podocyte structure that appear to underlie
many proteinuric renal diseases.

Reviews of clinical proteinuria, including causes, manifestations, and treatment of

specific glomerular disease, are presented separately. (See "Epidemiology,
classification, and pathogenesis of focal segmental glomerulosclerosis" and "Treatment
of primary focal segmental glomerulosclerosis".)

GLOMERULAR CAPILLARY WALL — To better appreciate the biology of glomerular

podocytes, it is important to understand the structural and functional anatomy of the
glomerular capillary wall.

The glomerular capillary wall, through which the filtrate must pass, consists of the
following three layers:

●Fenestrated capillary endothelium, extensively coated with a layer of polyanionic

glycosoaminoglycans and glycoproteins.
●Glomerular basement membrane (GBM), containing heparin sulfate and other
anionic glycosoaminoglycans.
●Podocytes (or epithelial cells), which are attached to the GBM by discrete foot
processes. The pores between the foot processes (slit pores) are closed by a thin
membrane called the slit diaphragm, which functions as a modified adherens
junction and may also be permeated by anatomical pores [10].

Defects in any of the three components of the glomerular capillary wall can lead to
proteinuria (picture 1) [11-13]. In addition, cross-talk between podocytes and
endothelial and mesangial cells are key to the maintenance of glomerular capillary wall
function. As examples, the production of vascular endothelial growth factor (VEGF) by
podocytes is necessary for the integrity of the glomerular endothelium [14], and the
upregulation and secretion of the podocyte protein, angiopoietin-like-4 (Angptl4) into
the glomerular capillary wall causes marked proteinuria in experimental models of
nephrotic syndrome [15].

PODOCYTES — Podocytes are terminally differentiated epithelial cells that have large
cell bodies and long primary or major processes. The primary processes attach to the
underlying GBM via multiple foot processes. Adhesion molecules, such as alpha3beta1
integrin complex and dystroglycan (which are present on the basal membrane of foot
processes), attach the podocyte to the GBM [16].
Slit diaphragm — The interdigitating foot processes of adjacent podocytes are joined
laterally by slit diaphragms that bridge the intervening filtration slits. The following
proteins have been found to comprise the slit diaphragm [17]:

●Nephrin [18]
●Neph1 and Neph2 [19-22]
●FAT1 and FAT 2 [23]
●Podocin [24]
●Transient receptor potential cation channel 6 (TRPC6) [25,26].
●Tight junction proteins, including junctional adhesion molecule A, occludin and
cingulin [27]

Slit diaphragms interact with the actin cytoskeleton of podocyte foot processes via
linker proteins. These include CD2-associated protein (CD2AP) [28-30], Nck [31,32],
zona occludens-1, and the catenins. Selective deletion of Nck expression in podocytes
of adult mice rapidly leads to proteinuria, glomerulosclerosis, and altered morphology
of foot processes [33]. Mutations of some of the genes that encode slit diaphragm
proteins cause rearrangement of the actin cytoskeleton, which results in foot process
effacement and proteinuria [33].

Nephrin and Neph1 also interact directly with the Par3-aPKC protein complex at the
podocyte intercellular junction, suggesting that this complex plays a key role in the
establishment and maintenance of podocyte polarity as it does in other polarized
epithelia and neurons [34-36].

Reviews of the evidence showing that abnormalities of these proteins are causative in
some congenital disorders are presented separately. (See "Congenital and infantile
nephrotic syndrome" and "Epidemiology, classification, and pathogenesis of focal
segmental glomerulosclerosis".)

Actin cytoskeleton — Podocyte architecture is maintained by a contractile apparatus

composed of microfilaments comprising actin, type I and type II myosins, alpha-actinin,
talin, paxillin, and vinculin, and palladin [37,38]. This cytoskeleton helps to support the
glomerular capillary wall, which is subject to the high hydrostatic pressure necessary
for glomerular filtration and plays a key role in the foot process architecture (figure 1).
The actin cytoskeleton also contributes to the highly motile character of these
specialized cells.

Immunofluorescence and confocal microscopy have demonstrated two distinct actin

cytoskeletal networks present in the foot processes [39]:

●Dense actin bundles are present above the level of the slit diaphragm and
extend parallel to the longitudinal axis.
●A cortical actin network extends just below the plasma membrane of the foot
processes.
Different actin-binding proteins are associated with each of these networks. Thus,
whereas alpha-actinin and synaptopodin are associated with the actin bundles above
the slit diaphragm, the cortical actin network co-localizes with cortactin [39].

Foot process effacement — Flattening of foot processes or foot process effacement

is a characteristic histologic finding associated with most primary and secondary
glomerular diseases. Rearrangement of the actin cytoskeleton is necessary for foot
process effacement to occur and stabilization of the actin cytoskeleton decreases
proteinuria. The actin cytoskeleton is a fluid structure that can be quickly and reversibly
reorganized. It is a direct target of cyclosporine A, which is an effective treatment for
reducing nephrotic range proteinuria among patients with minimal change disease [40].
The effect of cyclosporine A on the cytoskeleton is independent of (though does not
exclude) its effect on T cell dysfunction [40].

Actin is normally organized into coordinated stress fibers in mature foot processes.
Podocyte injury causes the rearrangement of actin to a dense network [16].

The cytoskeleton can be altered by at least four different mechanisms:

●Direct injury of podocytes can occur by systemic or locally produced toxins (ie,
reactive oxygen species), viral infection, drugs (pamidronate, interferon) or local
activation of the renin angiotensin system [41].
●Abnormalities of cytoskeletal structural proteins can adversely affect cytoskeletal
dynamics. An example is mutations of alpha-actinin-4, which cause hereditary
focal segmental glomerular sclerosis [42]. This abnormality increases the affinity
of alpha-actinin-4 for actin, which may alter cytoskeletal fluidity.
(See "Epidemiology, classification, and pathogenesis of focal segmental
glomerulosclerosis".)

The disruption of myosin 1e in mice promotes podocyte injury with foot process
effacement [43]. Genetic variations in the MYH9 locus are associated with
progressive nondiabetic proteinuric kidney disease in African Americans [44,45].
MYH9 encodes nonmuscle myosin heavy chain type II isoform A, expressed by
podocytes and other cells in the kidney. (See "Epidemiology, classification, and
pathogenesis of focal segmental glomerulosclerosis", section on 'FSGS in African
Americans'.)
●Injury to the slit diaphragm, arising from congenital or acquired disorders, can
initiate abnormal actin and nephrin signaling, resulting in cytoskeletal
reorganization [11,16-18,21,22,46].
●Changes in the structure of the GBM may lead to cytoskeletal derangements, as
observed in laminin beta 2 deficient mice, in which proteinuria precedes foot
process effacement [47].

Direct podocyte injury — Podocytes may be direct targets of injury in acquired

proteinuric diseases [48]. Injury may be immunologic or non-immunologic. An example
of an immunologic cause of podocyte injury is the effect of interleukin-13 (IL-13)
[49,50]. Accumulating data have suggested that IL-13 is a permeability factor that
causes minimal change disease. (See "Etiology, clinical features, and diagnosis of
minimal change disease in adults".) Isolated human and rat glomeruli and cultured
human and rat podocytes express receptors for IL-13, and the exposure of cells to IL-
13 initiates intracellular signaling, changes in transepithelial resistance, and changes in
protein trafficking [49,50]. These data suggest that a direct effect of IL-13 on podocytes
may underlie minimal change disease.

Non-immunologic causes of podocyte injury include viral infection (specifically HIV),

drug toxicity (eg, pamidronate), local activation of the renin-angiotensin system (RAS),
and reactive oxygen species (ROS).

HIV nephropathy is characterized by collapsing focal segmental glomerulosclerosis.

(See "HIV-associated nephropathy (HIVAN)".)

Clinical studies and animal models have shown that the podocyte is directly infected by
HIV genes and may provide a reservoir for replicating virus [51,52]. Exogenous
expression of HIV genes, Nef and Vpr, causes dedifferentiation, proliferation and loss
of contact inhibition, and apoptosis of podocytes [51-58]. Some believe that parvo B19
virus may have similar toxic effects as HIV on podocyte [48].

Inhibition of systemic RAS limits the progression of chronic kidney disease in the
setting of proteinuria [59]. This is due, in part, to a reduction of transglomerular
pressure. However, locally produced angiotensin may also have direct toxic effects on
the podocyte. Angiotensin receptors -1 and -2 are expressed by podocytes [60].
Mechanical strain of cultured podocytes increases expression of the angiotensin
receptor-1 as well as angiotensin-II and enhances podocyte apoptosis, which is
abrogated by angiotensin receptor blockade [41]. Furthermore, a transgenic rat that
overexpresses the angiotensin receptor-1, specifically in podocytes, is characterized by
proteinuria and structural changes in the podocyte that include effacement and
detachment [61].

Reactive oxygen species are produced in a number of conditions including puromycin

aminonucleoside nephrosis [62], complement activation, and metabolic disorders such
as obesity. In obese patients that are prone to develop focal segmental
glomerulosclerosis, albuminuria is negatively correlated with plasma adiponectin, while
adiponectin knock-out mice exhibit albuminuria and effacement of podocyte foot
processes. The protective effect of adiponectin seems to occur through activation of
adiponectin receptors expressed on the podocyte membrane and reduction of oxidative
stress [63].

A number of signaling pathways may lead to podocyte injury and proteinuria. In human
proteinuric kidney diseases such as diabetic nephropathy and focal segmental
glomerulosclerosis, upregulation of Wnt1 and active beta-catenin is observed in
podocytes, while podocyte-specific knock-out of beta-catenin protects against
development of albuminuria [64]. Podocytes possess the complete machinery for
glutamatergic signaling, and derangements in that signaling may lead to proteinuric
kidney diseases [65]. The Notch pathway seems to be involved in the development of
proteinuria because Notch intracellular domain is detected in injured podocytes and
genetic inactivation or pharmacologic inhibition of Notch ameliorates proteinuria and
podocyte damage [66].

Podocyte-specific deletion of Dicer, an enzyme that generates microRNA (small,

noncoding RNA that function as important regulators of gene expression) alters
cytoskeletal dynamics, and induces proteinuria and glomerulosclerosis [67,68].

Podocyte depletion — A decrease in podocyte number resulting from apoptosis or

detachment from the GBM may contribute to proteinuria and progressive
glomerulosclerosis [69-72]. In many glomerular disorders that are characterized by
hypertrophy, the volume of the glomerular tuft increases, despite the decrease in
podocyte number [71]. The resulting decrease in podocyte density causes areas of
denuded GBM, which are foci for adhesions to parietal epithelial cells and eventual
crescent formation [70].

Cytoskeletal rearrangement — The mechanism by which podocyte injury or

mutations in genes for slit diaphragm proteins initiate rearrangement of the
cytoskeleton is unclear. Similar intracellular events, such as phosphorylation of
constituent proteins, appear to occur during development of the foot processes and
after podocyte injury. During podocyte differentiation, for example, nephrin is transiently
phosphorylated on multiple tyrosine residues by the Src family kinase, Fyn [31].
Phosphorylation of nephrin allows its interaction with Nck, which is required for actin
reorganization [73]. Decreased nephrin phosphorylation may occur following podocyte
injury [31-33].

Another possible mechanism of cytoskeletal rearrangement is via the degradation of

dynamin, a GTPase protein that is generally considered to have a key role in deforming
cellular membranes. Dynamin associates with actin, possibly via the actin-binding
protein, cortactin [74,75].

Cleavage of dynamin by cathepsin-L may initiate reorganization of the cytoskeleton,

resulting in clinical disease. Support for this is provided by findings in animal models
and some human glomerular diseases [76,77] (figure 2):

●Levels of cathepsin-L were found to be increased in a murine model of minimal

change disease [76]. This increase has also been observed in patients with
membranous nephropathy, focal segmental glomerulosclerosis, and diabetic
nephropathy, although significant increases were not found in those with other
proteinuric kidney diseases [77].
●Proteinuria and foot process effacement induced by lipopolysaccharide are
abrogated in cathepsin-L-knockout mice [76].
●Whereas the expression of a cathepsin-L-degraded dynamin fragment causes
foot process effacement and proteinuria, the expression of cathepsin-L-resistant
dynamin mutants decreases proteinuria

Cytoskeletal rearrangement may also be induced by the urokinase receptor (uPAR) via
its activation of the vitronectin receptor, alphavbeta3 integrin [78]. The absence of
uPAR, beta3 integrin or the alphavbeta3 integrin ligand, vitronectin, protects mice from
 developing lipopolysaccharide-induced proteinuria. This protection is abolished by
exogenous expression of either uPAR or a constitutively active beta3 integrin [78].
uPAR may be required to activate alphavbeta3 integrin in podocytes promoting cell
motility and activation of small GTPases.

Proteinuria as a toxin — Although massive proteinuria may occur in the absence of

obvious structural change in the slit diaphragm and foot processes, sustained
proteinuria event is invariably eventually associated with foot process effacement
[47,79-82]. The mechanism underlying this phenomenon is unclear. One possibility is
that exposure of podocytes to an increased concentration of albumin and IgG is
sufficient to induce changes in the cytoskeleton [83].

SUMMARY

●The glomerular capillary wall consists of the fenestrated capillary endothelium,

glomerular basement membrane (GBM), and glomerular podocytes (or epithelial
cells). Defects in any of the three components of the glomerular capillary wall can
lead to proteinuria. (See 'Glomerular capillary wall' above.)
●Glomerular podocytes are terminally differentiated epithelial cells that have large
cell bodies and long primary or major processes. The primary processes attach to
the underlying GBM via multiple foot processes. (See 'Podocytes' above.)
●The interdigitating foot processes of adjacent podocytes are joined laterally by
slit diaphragms that bridge the intervening filtration slits. A number of proteins
have been found to comprise the slit diaphragm; these include nephrin, neph1,
neph2, FAT1, FAT 2, podocin, TRPC6 and tight junction proteins. (See 'Slit
diaphragm' above.)
●Foot process effacement of glomerular podocytes is a characteristic histologic
finding associated with glomerular diseases affecting the podocyte.
Rearrangement of the actin cytoskeleton is necessary for foot process effacement
to occur. (See 'Foot process effacement'above.)
●Possible molecular mechanisms underlying cytoskeletal rearrangement
include phosphorylation/dephosphorylation of nephrin and cleavage of dynamin (a
GTPase protein) by cathepsin-L. Activation of the urokinase receptor (uPAR) and
initiation of beta3 integrin signaling may also be involved (see 'Cytoskeletal
rearrangement' above).
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