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2006 International Society of Nephrology

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microalbuminuria and confer renal and

The PPAR ligand fenofibrate: cardiovascular protection. However, a
major factor limiting the use of TZDs
meeting multiple targets in for their renal and cardiac protection
in diabetic patients is fluid retention. It
diabetic nephropathy has been suggested that TZDs activate
PPAR expression at the collecting duct,
Z Varghese1, JF Moorhead1 and XZ Ruan1 which enhances expression of cell-surface
epithelial sodium channel .5 Studies in
Fibrate peroxisome proliferator-activated receptor (PPAR)- ligands are healthy men have shown that pioglita-
mainly used as hypolipidemic drugs. But this commentary highlights zone stimulates plasma renin activity
their potential in treating insulin resistance, dyslipidemia, and that contributes to sodium retention and
hypertension and in preventing diabetic nephropathy, inflammation, weight gain.
It is in this context that we should pay
and cardiovascular disease. Because diabetes is a major contributor to
special attention to a study on the db/db
chronic kidney disease and cardiovascular disease, PPAR- agonists mouse model of diabetes published in
may provide greater opportunities for hitting multiple targets in this this issue of Kidney International by Park
complex metabolic disease. et al.6, who demonstrate that fenofibrate,
Kidney International (2006) 69, 14901491. doi:10.1038/sj.ki.5000180 a PPAR agonist, reduces fasting blood
glucose, ameliorates insulin resistance,
reduces hypertrophy of pancreatic islets,
Currently, there are more than 177 mil- sensitizing thiazolidinediones (TZDs) are and reduces urinary albumin excretion.
lion people with diabetes worldwide, and increasingly used in type 2 diabetes. TZDs Park et al. show that the renal protec-
it is projected that this will rise to 360 are ligands for peroxisome proliferator- tion afforded by fenofibrate may occur
million by 2030.1 Considering that 30% activated receptor- (PPAR), a member through the reduction of glomerular
of these people may develop chronic kid- of the ligand-dependent nuclear recep- hypertrophy and mesangial matrix. These
ney disease, which is also a major inde- tor superfamily. After ligand binding, data suggest that PPAR agonists may
pendent risk factor for cardiovascular PPARs form heterodimers with retinoid represent a potential therapeutic target
disease, it is clear that early detection and X receptor- and then undergo confor- in treating type 2 diabetes and its renal
prevention are the only means of escape mational changes, which facilitate their complications without fluid retention and
from this emerging medical catastrophe binding to PPAR-responsive elements in weight gain.
of worldwide proportions. Current treat- the nucleus for target gene transcription. In 1982 Moorhead and colleagues
ment protocols involving tight glucose PPARs play an important role in the gen- introduced the concept of lipid-medi-
and blood pressure control, inhibition of eral transcriptional control of numerous ated renal injury and suggested how
the reninangiotensin system, and lipid cellular processes that are key factors in the pathogenesis of atherosclerosis and
lowering have achieved only a modest, the development of diabetic nephropa- glomerulosclerosis could have common
though encouraging, impact in arresting thy, including glucose homeostasis, lipid pathways. They have further shown how
the development and progression of dia- metabolism, cell differentiation, cell cycle inflammation could modify lipid-medi-
betic nephropathy. Additional strategies progression, extracellular matrix mod- ated renal injury by increasing cholesterol
with multiple drugs seem to be essential eling, and inflammatory signals. uptake and inhibiting cholesterol efflux
to deal with this impending pandemic. All three isoforms of PPARs PPAR, in human mesangial cells and smooth
Insulin resistance is a key factor mediating PPAR, and PPAR/ are highly muscle cells.7 Lipid-mediated injury plays
vascular injury and nephropathy in type expressed in mesangial cells, proximal an important role in the pathogenesis of
2 diabetes mellitus; it has a role in type 1 tubules, and the medullary collecting many renal diseases, including diabetic
as well. It is for this reason that insulin- duct.2 It has been demonstrated that nephropathy. Diabetic kidneys specifi-
PPAR mRNA is reduced by 77% in cally expressed several genes normally
1Centre for Nephrology, Royal Free and University glomeruli of diabetic mice,3 and insu- found in adipocytes, including adipose
College Medical School, University College London, lin-sensitizing TZDs are used for treat- differentiation-related protein (ADRP,
London, UK ing diabetes and metabolic syndrome. or adipophilin in humans), suggesting a
Correspondence: Z Varghese, Centre for TZDs also provide renal protection in a switch of kidney phenotype in favor of
Nephrology, Royal Free and University College rat model of type 2 diabetes with obesity lipid accumulation in diabetes.8
Medical School, University College London, Royal
Free Campus, Rowland Hill Street, London NW3
by reducing proteinuria and glomerular It has been demonstrated that PPARs
2PF, UK. and tubular kidney damage.4 In patients play an important role in controlling cel-
E-mail: z.varghese@medsch.ucl.ac.uk with type 2 diabetes, TZDs ameliorate lular and whole-body sterol homeostasis,

1490 Kidney International (2006) 69


including fatty acid, triglyceride, and
lipoprotein metabolism and reverse cho-
lesterol transport. Binding to PPAR by
fatty acids, eicosanoids, and drug ligands
leads to activation of numerous genes
involved in the uptake and -oxidative
catabolism of fatty acids in the heart,
kidney, and muscle. Increased diversion
of fatty acids into -oxidation decreases
the availability of fatty-acyl-coenzyme A
substrates for triglyceride synthesis and,
therefore, reduces secretion of very-low-
density lipoprotein by the liver. PPAR
agonists may also decrease triglyceride
levels by increasing the expression of
lipoprotein lipase in the liver (PPAR),
in adipocytes and skeletal muscle
(PPAR), and in macrophages (PPAR
and PPAR). It is rather surprising that
fenofibrate at the dose used in this model
does not reduce triglycerides. This may
be due to an increase in very-low-density
lipoprotein synthesis through the path-
way of sterol regulatory element-binding
protein-1c (SREBP1c), another PPAR-
targeted gene, rather than to a reduction
in -oxidation of fatty acid with PPAR
agonists. Interestingly, serum total cho-
lesterol levels increase in db/db mice
after 8 weeks of treatment. However, the
lipid profiles of these mice show that the
major cholesterol subfraction affected
by fenofibrate is composed of increased
high-density lipoprotein cholesterol.
This could be a consequence of the fact
that PPAR agonists increase cholesterol
efflux from the peripheral tissue through
the ABCA1 pathway, as demonstrated
by Ruan et al.7 In addition, high-density
lipoprotein reduces the low-density lipo-
protein influx into the cells by reducing
the expression of CD36, and inhibiting
the oxidation of low-density lipoprotein
molecules. To further prove this, it will
be important to investigate how PPAR
specifically affects cholesterol reverse
transport from peripheral tissues to the
liver, and also how PPAR affects the
liver x receptorSREBP1c pathway that
controls triglyceride synthesis. Perhaps
a more specific PPAR agonist, which
specifically targets the liver x receptor
ABCA1 pathway rather than SREBP1c,
will be required.
We have previously demonstrated that
bezafibrate can override the suppression
Kidney International (2006) 69
of inflammatory cytokine-induced reduc-
tion of cholesterol efflux and prevent lipid
accumulation in human mesangial cells.7
Presumably, it also increases bile acid syn-
thesis and cholesterol absorption, which
may contribute to dyslipidemia in patients
with chronic renal diseases. We have also
observed that bezafibrate inhibits NF-
B activation and cytokine expression
in human mesangial cells (unpublished
data). It is possible that fenofibrate will
improve the renal and cardiac protection
afforded by bezafibrate by increasing
both its anti-inflammatory effects and
the high-density lipoprotein-mediated
cholesterol efflux pathway.
Diabetic glomerulosclerosis is char-
acterized by the accumulation of extra-
cellular matrix in the mesangium.
Troglitazone, a PPAR agonist, sup-
presses the secretion of type I collagen by
mesangial cells in vitro; it also prevents
mesangial expansion and glomerulo-
sclerosis in diabetic rats.9 Interestingly,
Park et al. demonstrate in this issue that
fenofibrate, a PPAR agonist, also reduces
urinary albumin excretion and provides
renal protection through the reduction of
glomerular hypertrophy and mesangial
matrix accumulation; this suggests that
PPAR may represent a potential thera-
peutic target in the treatment of type 2
diabetes and its renal complications.
Hypertension is commonly associated
with insulin resistance, making blood
pressure control an essential target for
delaying the progression of diabetic
nephropathy. The renoprotective effect of
angiotensin-converting enzyme inhibi-
tors and angiotensin-2 receptor blockers,
which is partially independent of blood
pressure reduction, is well established in
clinical practice. The antihypertensive
effect of the PPAR agonist rosiglita-
zone has been reported in patients with
diabetes or obesity. Cytochrome P450-
dependent arachidonic acid metabolites
may act as mediators in the regulation of
vascular tone and renal function. It has
been shown that both PPAR and cyto-
chrome P450 4A are expressed in renal
proximal tubules. Treatment with either
of the PPAR agonists clofibrate and
bezafibrate increased cytochrome P450
4A protein levels and production of 20-
hydroxyarachidonic acid (20-HETE)10
co m m e nta r y
and thus may ameliorate hypertension
by restoring cytochrome P450-dependent
arachidonic acid hydroxylase activities.
Diabetes is a major contributor to
chronic kidney disease (CKD), and
CKD patients are considered to be at
the highest risk for cardiovascular dis-
ease. Clinical studies are beginning to
emerge that support the hypothesis that
the correction of dyslipidemia associated
with CKD may slow the progression of
cardiovascular disease. The emerging
understanding of the interplay of insulin
resistance, CKD, and cardiovascular dis-
ease is providing interesting possibilities
for resolving some of the major metabolic
consequences of the pandemic outbreak
of type 2 diabetes. Therefore, develop-
ment of strategies for early detection of
insulin resistance and treatment with
drugs that have multiple targets has great
potential for tackling diabetes, CKD, and
cardiovascular disease.
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