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

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