Renoprotective effect of a novel selective PPARα modulator K-877 in db/db mice: A role of diacylglycerol-protein kinase C-NAD(P)H oxidase pathway

Metabolism: Clinical and Experimental
Toshinobu MakiToyoshi Inoguchi

Abstract

Several clinical studies have shown the beneficial effects of peroxisome proliferator-activated receptor α (PPARα) agonists on diabetic nephropathy. However, the molecular mechanism is not fully understood. Here we show that K-877, a novel selective PPARα modulator, ameliorates nephropathy in db/db mice via inhibition of renal lipid content and oxidative stress. K-877 (0.5mg/kg/day) was administered to db/db mice for 2 or 12weeks. Short-term treatment did not affect body weight or plasma glucose levels in db/db mice, but attenuated albuminuria, along with improvement of plasma lipid profiles, lipid content including total diacylglycerol (DAG) levels, protein kinase C (PKC) activity, NAD(P)H oxidase-4 expression, and oxidative stress markers, all of which were significantly increased in diabetic kidneys. It increased phosphorylation of 5'-AMP activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), and expression of several genes mediating fatty acid β-oxidation. In addition, long-term treatment ameliorated renal mesangial expansion in db/db mice and improved glycemic control. K-877 administration ameliorates diabetic nephropathy, at least in part, via inhibition of renal lipid content and oxidative stress. The underlyi...Continue Reading

Citations

Jul 19, 2018·Endocrine Reviews·Nadia BougarneKarolien De Bosscher
Oct 3, 2019·Current Opinion in Lipidology·Jean-Charles Fruchart, Raul D Santos
May 20, 2020·Current Opinion in Nephrology and Hypertension·Ronak Lakhia
Sep 6, 2017·Frontiers of Medicine·Qiuxia HanZhangsuo Liu
Apr 2, 2019·Journal of Atherosclerosis and Thrombosis·Shizuya YamashitaYuji Matsuzawa
Nov 27, 2019·International Journal of Molecular Sciences·Yusuke SasakiTatsuhiko Kodama

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