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.
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The effect on lung function and respiratory symptoms of reducing of consumption of conventional cigarettes by switching to electronic cigarettes is investigated by the Cibella et al. in their Clinical Science research article on pages 1929-1937 (volume 130, issue 21).
Research Article|
September 30 2016
Peroxisome proliferator-activated receptor α-dependent renoprotection of murine kidney by irbesartan
Makoto Harada;
Makoto Harada
*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
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Yuji Kamijo;
*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
Correspondence: Yuji Kamijo (email [email protected]).
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Takero Nakajima;
Takero Nakajima
†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
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Koji Hashimoto;
Koji Hashimoto
*Department of Nephrology, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, Nagano, 390-8621, Japan
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Yosuke Yamada;
Yosuke Yamada
*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
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Hisashi Shimojo;
Hisashi Shimojo
‡Department of Pathology, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, Nagano, 390-8621, Japan
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Frank J. Gonzalez;
Frank J. Gonzalez
§Laboratory of Metabolism, National Cancer Institute, Bethesda, MD 20892, U.S.A.
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Toshifumi Aoyama
Toshifumi Aoyama
†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
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Publisher: Portland Press Ltd
Received:
May 18 2016
Revision Received:
July 19 2016
Accepted:
August 05 2016
Accepted Manuscript online:
August 05 2016
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society
2016
Clin Sci (Lond) (2016) 130 (21): 1969–1981.
Article history
Received:
May 18 2016
Revision Received:
July 19 2016
Accepted:
August 05 2016
Accepted Manuscript online:
August 05 2016
Citation
Makoto Harada, Yuji Kamijo, Takero Nakajima, Koji Hashimoto, Yosuke Yamada, Hisashi Shimojo, Frank J. Gonzalez, Toshifumi Aoyama; Peroxisome proliferator-activated receptor α-dependent renoprotection of murine kidney by irbesartan. Clin Sci (Lond) 1 November 2016; 130 (21): 1969–1981. doi: https://doi.org/10.1042/CS20160343
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