The peroxisome proliferator-activated receptor-α agonist, BAY PP1, attenuates renal fibrosis in rats

Recent studies have shown renoprotective effects of the peroxisome proliferator-activated receptor-alpha (PPAR-alpha), but its role in kidney fibrosis is unknown. In order to gain insight into this, we examined the effect of a novel PPAR-alpha agonist, BAY PP1, in two rat models of renal fibrosis: unilateral ureteral obstruction and the 5/6 nephrectomy. In healthy animals, PPAR-alpha was expressed in tubular but not in interstitial cells. Upon induction of fibrosis, PPAR-alpha was significantly downregulated, and treatment with BAY PP1 significantly restored its expression. During ureteral obstruction, treatment with BAY PP1 significantly reduced tubulointerstitial fibrosis, proliferation of interstitial fibroblasts, and TGF-beta(1) expression. Treatment with a less potent PPAR-alpha agonist, fenofibrate, had no effects. Treatment with BAY PP1, initiated in established disease in the 5/6 nephrectomy, halted the decline of renal function and significantly ameliorated renal fibrosis. In vitro, BAY PP1 had no direct effect on renal fibroblasts but reduced collagen, fibronectin, and TGF-beta(1) expression in tubular cells. Conditioned media of BAY PP1-treated tubular cells reduced fibroblast proliferation. Thus, renal fibrosis is characterized by a reduction of PPAR-alpha expression, and treatment with BAY PP1 restores PPAR-alpha expression and ameliorates renal fibrosis by modulating the cross-talk between tubular cells and fibroblasts. Hence, potent PPAR-alpha agonists might be useful in the treatment of renal fibrosis. Kidney International (2011) 80, 1182-1197; doi:10.1038/ki.2011.254; published online 3 August 2011