title: Peroxisome proliferator-activated receptor α-dependent renoprotection of murine kidney by irbesartan.
abstract: Activation of renal peroxisome proliferator-activated receptor α (PPARα) is renoprotective, but there is no safe PPARα activator for patients with chronic kidney disease (CKD). Studies have reported that irbesartan (Irbe), an angiotensin II receptor blocker (ARB) widely prescribed for CKD, activates hepatic PPARα. However, Irbe's renal PPARα-activating effects and the role of PPARα signalling in the renoprotective effects of Irbe are unknown. Herein, these aspects were investigated in healthy kidneys of wild-type (WT) and Ppara-null (KO) mice and in the murine protein-overload nephropathy (PON) model respectively. The results were compared with those of losartan (Los), another ARB that does not activate PPARα. PPARα and its target gene expression were significantly increased only in the kidneys of Irbe-treated WT mice and not in KO or Los-treated mice, suggesting that the renal PPARα-activating effect was Irbe-specific. Irbe-treated-PON-WT mice exhibited decreased urine protein excretion, tubular injury, oxidative stress (OS), and pro-inflammatory and apoptosis-stimulating responses, and they exhibited maintenance of fatty acid metabolism. Furthermore, the expression of PPARα and that of its target mRNAs encoding proteins involved in OS, pro-inflammatory responses, apoptosis and fatty acid metabolism was maintained upon Irbe treatment. These renoprotective effects of Irbe were reversed by the PPARα antagonist MK886 and were not detected in Irbe-treated-PON-KO mice. These results suggest that Irbe activates renal PPARα and that the resultant increased PPARα signalling mediates its renoprotective effects.
authors: Department of Nephrology, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, Nagano, 390-8621, Japan Department of Metabolic Regulation, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, 3-1-1, Asahi, Matsumoto, Nagano, 390-8621, Japan.
authors: Makoto
authors: M
authors: Harada
authors: Department of Nephrology, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, Nagano, 390-8621, Japan Department of Metabolic Regulation, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, 3-1-1, Asahi, Matsumoto, Nagano, 390-8621, Japan yujibeat@shinshu-u.ac.jp.
authors: Yuji
authors: Y
authors: Kamijo
authors: Department of Metabolic Regulation, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, 3-1-1, Asahi, Matsumoto, Nagano, 390-8621, Japan.
authors: Takero
authors: T
authors: Nakajima
authors: Department of Nephrology, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, Nagano, 390-8621, Japan.
authors: Koji
authors: K
authors: Hashimoto
authors: Department of Nephrology, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, Nagano, 390-8621, Japan Department of Metabolic Regulation, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, 3-1-1, Asahi, Matsumoto, Nagano, 390-8621, Japan.
authors: Yosuke
authors: Y
authors: Yamada
authors: Department of Pathology, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, Nagano, 390-8621, Japan.
authors: Hisashi
authors: H
authors: Shimojo
authors: Laboratory of Metabolism, National Cancer Institute, Bethesda, MD 20892, U.S.A.
authors: Frank J
authors: FJ
authors: Gonzalez
authors: Department of Metabolic Regulation, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, 3-1-1, Asahi, Matsumoto, Nagano, 390-8621, Japan.
authors: Toshifumi
authors: T
authors: Aoyama
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage*; D006801:Humans; D000077405:Irbesartan; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D020011:Protective Agents / Q000008:administration & dosage*; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D013777:Tetrazoles / Q000008:administration & dosage*
chemical_list: D001713:Biphenyl Compounds; D047493:PPAR alpha; D020011:Protective Agents; D013777:Tetrazoles; D000077405:Irbesartan
keywords: angiotensin II type 1 receptor blocker; fatty acid metabolism; irbesartan (Irbe); peroxisome proliferator-activated receptor α (PPARα)