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

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.

• Authors: Peter Boor, Peter Celec, Ina V Martin, Luigi Villa, Július Hodosy, Kristína Klenovicsová, Ciro Esposito, Stefan Schäfer, Barbara Albrecht-Küpper, Tammo Ostendorf, August Heidland, Katarína Šebeková
• Journal: Kidney international (Kidney Int) Vol. 80 Issue 11 Pg. 1182-97 (Dec 2011) ISSN: 1523-1755 [Electronic] United States
• PMID: 21814170 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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