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

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