Toshinobu Maki1, Yasutaka Maeda2, Noriyuki Sonoda2, Hiroaki Makimura1, Shinichiro Kimura1, Sayaka Maeno1, Ryoichi Takayanagi1, Toyoshi Inoguchi3. 1. Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 2. Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan. 3. Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan. Electronic address: toyoshi@med.kyushu-u.ac.jp.
Abstract
OBJECTIVE: 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. METHODS AND RESULTS: 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. CONCLUSIONS: K-877 administration ameliorates diabetic nephropathy, at least in part, via inhibition of renal lipid content and oxidative stress. The underlying mechanism may be mediated by modulating the renal AMPK-ACC pathway, subsequent acceleration of fatty acid β-oxidation and inhibition of fatty acid synthesis, and thus inhibition of the DAG-PKC-NAD(P)H oxidase pathway, in addition to its systemic effect including improvement of the plasma lipid profile and glycemic control.
OBJECTIVE: 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. METHODS AND RESULTS: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. CONCLUSIONS:K-877 administration ameliorates diabetic nephropathy, at least in part, via inhibition of renal lipid content and oxidative stress. The underlying mechanism may be mediated by modulating the renal AMPK-ACC pathway, subsequent acceleration of fatty acid β-oxidation and inhibition of fatty acid synthesis, and thus inhibition of the DAG-PKC-NAD(P)H oxidase pathway, in addition to its systemic effect including improvement of the plasma lipid profile and glycemic control.
Authors: Jean-Charles Fruchart; Raul D Santos; Carlos Aguilar-Salinas; Masanori Aikawa; Khalid Al Rasadi; Pierre Amarenco; Philip J Barter; Richard Ceska; Alberto Corsini; Jean-Pierre Després; Patrick Duriez; Robert H Eckel; Marat V Ezhov; Michel Farnier; Henry N Ginsberg; Michel P Hermans; Shun Ishibashi; Fredrik Karpe; Tatsuhiko Kodama; Wolfgang Koenig; Michel Krempf; Soo Lim; Alberto J Lorenzatti; Ruth McPherson; Jesus Millan Nuñez-Cortes; Børge G Nordestgaard; Hisao Ogawa; Chris J Packard; Jorge Plutzky; Carlos I Ponte-Negretti; Aruna Pradhan; Kausik K Ray; Željko Reiner; Paul M Ridker; Massimiliano Ruscica; Shaukat Sadikot; Hitoshi Shimano; Piyamitr Sritara; Jane K Stock; Ta-Chen Su; Andrey V Susekov; André Tartar; Marja-Riitta Taskinen; Alexander Tenenbaum; Lale S Tokgözoğlu; Brian Tomlinson; Anne Tybjærg-Hansen; Paul Valensi; Michal Vrablík; Walter Wahli; Gerald F Watts; Shizuya Yamashita; Koutaro Yokote; Alberto Zambon; Peter Libby Journal: Cardiovasc Diabetol Date: 2019-06-04 Impact factor: 9.951