title: 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.affiliation: Department of Clinical and Experimental Pharmacotherapy, Research Base of Slovak Medical University, Bratislava, Slovakia. boor@email.cz
authors.forename: Peter
authors.initials: P
authors.lastname: Boor
authors.forename: Peter
authors.initials: P
authors.lastname: Celec
authors.forename: Ina V
authors.initials: IV
authors.lastname: Martin
authors.forename: Luigi
authors.initials: L
authors.lastname: Villa
authors.forename: Július
authors.initials: J
authors.lastname: Hodosy
authors.forename: Kristína
authors.initials: K
authors.lastname: Klenovicsová
authors.forename: Ciro
authors.initials: C
authors.lastname: Esposito
authors.forename: Stefan
authors.initials: S
authors.lastname: Schäfer
authors.forename: Barbara
authors.initials: B
authors.lastname: Albrecht-Küpper
authors.forename: Tammo
authors.initials: T
authors.lastname: Ostendorf
authors.forename: August
authors.initials: A
authors.lastname: Heidland
authors.forename: Katarína
authors.initials: K
authors.lastname: Šebeková
mesh_terms: D015097:3-Mercaptopropionic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D005355:Fibrosis / Q000188:drug therapy / Q000517:prevention & control*; D007674:Kidney Diseases / Q000188:drug therapy* / Q000473:pathology; D007684:Kidney Tubules / Q000473:pathology; D009392:Nephrectomy; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists*; D020011:Protective Agents; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D016896:Treatment Outcome; D014517:Ureteral Obstruction / Q000188:drug therapy
chemical_list: C572615:2-((4-(((2-methoxyethyl)(6-(3-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)methyl)phenyl)sulfanyl)-2-methylpropanoic acid; D047492:Peroxisome Proliferator-Activated Receptors; D020011:Protective Agents; D011743:Pyrimidines; D015097:3-Mercaptopropionic Acid