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Proximal tubule PPARα attenuates renal fibrosis and inflammation caused by unilateral ureteral obstruction.
- Source :
-
American journal of physiology. Renal physiology [Am J Physiol Renal Physiol] 2013 Sep 01; Vol. 305 (5), pp. F618-27. Date of Electronic Publication: 2013 Jun 26. - Publication Year :
- 2013
-
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.
- Subjects :
- Animals
Arginase biosynthesis
Aristolochic Acids pharmacology
B7-2 Antigen biosynthesis
Collagen Type I biosynthesis
Collagen Type IV
Down-Regulation
Fibrosis
Interleukin-10 biosynthesis
Kidney Tubules, Proximal metabolism
Laminin biosynthesis
Mice
Mice, Transgenic
MicroRNAs biosynthesis
Nephritis prevention & control
PPAR alpha biosynthesis
Transforming Growth Factor beta biosynthesis
Kidney Diseases etiology
PPAR alpha physiology
Ureteral Obstruction complications
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1466
- Volume :
- 305
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Renal physiology
- Publication Type :
- Academic Journal
- Accession number :
- 23804447
- Full Text :
- https://doi.org/10.1152/ajprenal.00309.2013