Peroxisome proliferator-activated receptor ?-dependent renoprotection of murine kidney by irbesartan.

ABSTRACT: Activation of renal peroxisome proliferator-activated receptor ? (PPAR?) is renoprotective, but there is no safe PPAR? 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 PPAR?. However, Irbe's renal PPAR?-activating effects and the role of PPAR? 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 PPAR?. PPAR? 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 PPAR?-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 PPAR? 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 PPAR? antagonist MK886 and were not detected in Irbe-treated-PON-KO mice. These results suggest that Irbe activates renal PPAR? and that the resultant increased PPAR? signalling mediates its renoprotective effects.

SUBMITTER: Harada M 

PROVIDER: S-EPMC6331013 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature