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 signaling 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, 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 oxidative stress, 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 signaling mediates its renoprotective effects.
- peroxisome proliferator-activated receptor α (PPARα)
- angiotensin II type 1 receptor blocker
- fatty acid metabolism
- ©2016 The Author(s)
This is an Accepted Manuscript; not the final Version of Record. Archiving permitted only in line with the archiving policy of Portland Press Limited. All other rights reserved.