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Am J Physiol Renal Physiol. 2013 Sep 1;305(5):F618-27. doi: 10.1152/ajprenal.00309.2013. Epub 2013 Jun 26.

Proximal tubule PPARα attenuates renal fibrosis and inflammation caused by unilateral ureteral obstruction.

Author information

1
Division of Nephrology, Univ. of Arkansas for Medical Sciences, 4301 West Markham St., Slot 501, Little Rock, AR 72205, USA.

Abstract

We examined the effects of increased expression of proximal tubule peroxisome proliferator-activated receptor (PPAR)α in a mouse model of renal fibrosis. After 5 days of unilateral ureteral obstruction (UUO), PPARα expression was significantly reduced in kidney tissue of wild-type mice but this downregulation was attenuated in proximal tubules of PPARα transgenic (Tg) mice. When compared with wild-type mice subjected to UUO, PPARα Tg mice had reduced mRNA and protein expression of proximal tubule transforming growth factor (TGF)-β1, with reduced production of extracellular matrix proteins including collagen 1, fibronectin, α-smooth muscle actin, and reduced tubulointerstitial fibrosis. UUO-mediated increased expression of microRNA 21 in kidney tissue was also reduced in PPARα Tg mice. Overexpression of PPARα in cultured proximal tubular cells by adenoviral transduction reduced aristolochic acid-mediated increased production of TGF-β, demonstrating PPARα signaling reduces epithelial TGF-β production. Flow cytometry studies of dissociated whole kidneys demonstrated reduced macrophage infiltration to kidney tissue in PPARα Tg mice after UUO. Increased expression of proinflammatory cytokines including IL-1β, IL-6, and TNF-α in wild-type mice was also significantly reduced in kidney tissue of PPARα Tg mice. In contrast, the expression of anti-inflammatory cytokines IL-10 and arginase-1 was significantly increased in kidney tissue of PPARα Tg mice when compared with wild-type mice subjected to UUO. Our studies demonstrate several mechanisms by which preserved expression of proximal tubule PPARα reduces tubulointerstitial fibrosis and inflammation associated with obstructive uropathy.

KEYWORDS:

interleukin-10; peroxisome proliferator-activated receptor; transforming growth factor-β

PMID:
23804447
PMCID:
PMC3761210
DOI:
10.1152/ajprenal.00309.2013
[Indexed for MEDLINE]
Free PMC Article

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