The Peroxisome Proliferator-Activated receptor-α Agonist, BAY PP1, Attenuates Renal Fibrosis in Rats

Kidney Int. 2011 Dec;80(11):1182-97. doi: 10.1038/ki.2011.254. Epub 2011 Aug 3.

Abstract

Recent studies have shown renoprotective effects of the peroxisome proliferator-activated receptor-α (PPAR-α), but its role in kidney fibrosis is unknown. In order to gain insight into this, we examined the effect of a novel PPAR-α agonist, BAY PP1, in two rat models of renal fibrosis: unilateral ureteral obstruction and the 5/6 nephrectomy. In healthy animals, PPAR-α was expressed in tubular but not in interstitial cells. Upon induction of fibrosis, PPAR-α 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-β(1) expression. Treatment with a less potent PPAR-α 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-β(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-α expression, and treatment with BAY PP1 restores PPAR-α expression and ameliorates renal fibrosis by modulating the cross-talk between tubular cells and fibroblasts. Hence, potent PPAR-α agonists might be useful in the treatment of renal fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Mercaptopropionic Acid / analogs & derivatives*
  • 3-Mercaptopropionic Acid / pharmacology
  • 3-Mercaptopropionic Acid / therapeutic use
  • Animals
  • Cell Proliferation / drug effects
  • Fibrosis / drug therapy
  • Fibrosis / prevention & control*
  • Kidney Diseases / drug therapy*
  • Kidney Diseases / pathology
  • Kidney Tubules / pathology
  • Nephrectomy
  • Peroxisome Proliferator-Activated Receptors / agonists*
  • Protective Agents
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use*
  • Rats
  • Treatment Outcome
  • Ureteral Obstruction / drug therapy

Substances

  • 2-((4-(((2-methoxyethyl)(6-(3-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)methyl)phenyl)sulfanyl)-2-methylpropanoic acid
  • Peroxisome Proliferator-Activated Receptors
  • Protective Agents
  • Pyrimidines
  • 3-Mercaptopropionic Acid