We examined the effects of increased expression of proximal tubule PPARα 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 Tg mice. When compared with wild type mice subjected to UUO, PPARα Tg mice had reduced mRNA and protein expression of proximal tubule TGFβ1, with reduced production of extracellular matrix proteins including collagen 1, fibronectin, α-SMA, and reduced tubulo-interstitial fibrosis. UUO-mediated increased expression of microRNA 21 (miR21) in kidney tissue was also reduced in PPARα Tg mice. Over-expression of PPARα in cultured proximal tubular cells by adenoviral transduction reduced aristolochic acid(AA)-mediated increased production of TGFβ, demonstrating PPARα signaling reduces epithelial TGFβ production. Flow cytometry studies of dissociated whole kidneys demonstrated reduced macrophage infiltration to kidney tissue in PPARα Tg mice after UUO. Increased expression of pro-inflammatory cytokines including IL1-β, 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 tubulo-interstitial fibrosis and inflammation associated with obstructive uropathy.