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

Toshinobu Maki, Yasutaka Maeda, Noriyuki Sonoda, Hiroaki Makimura, Shinichiro Kimura, Sayaka Maeno, Ryoichi Takayanagi, Toyoshi Inoguchi

研究成果: ジャーナルへの寄稿記事

10 引用 (Scopus)

抄録

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 (0.5 mg/kg/day) was administered to db/db mice for 2 or 12 weeks. 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.

元の言語英語
ページ(範囲)33-45
ページ数13
ジャーナルMetabolism: Clinical and Experimental
71
DOI
出版物ステータス出版済み - 6 1 2017

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Diacylglycerol Kinase
Peroxisome Proliferator-Activated Receptors
NADPH Oxidase
Protein Kinase C
Kidney
Lipids
Acetyl-CoA Carboxylase
AMP-Activated Protein Kinases
Oxidative Stress
Fatty Acids
Diabetic Nephropathies
Albuminuria
Diglycerides
Body Weight
Phosphorylation
Gene Expression
Glucose

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

これを引用

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. / Maki, Toshinobu; Maeda, Yasutaka; Sonoda, Noriyuki; Makimura, Hiroaki; Kimura, Shinichiro; Maeno, Sayaka; Takayanagi, Ryoichi; Inoguchi, Toyoshi.

:: Metabolism: Clinical and Experimental, 巻 71, 01.06.2017, p. 33-45.

研究成果: ジャーナルへの寄稿記事

Maki, Toshinobu ; Maeda, Yasutaka ; Sonoda, Noriyuki ; Makimura, Hiroaki ; Kimura, Shinichiro ; Maeno, Sayaka ; Takayanagi, Ryoichi ; Inoguchi, Toyoshi. / 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. 2017 ; 巻 71. pp. 33-45.
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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 (0.5 mg/kg/day) was administered to db/db mice for 2 or 12 weeks. 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.",
author = "Toshinobu Maki and Yasutaka Maeda and Noriyuki Sonoda and Hiroaki Makimura and Shinichiro Kimura and Sayaka Maeno and Ryoichi Takayanagi and Toyoshi Inoguchi",
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T1 - Renoprotective effect of a novel selective PPARα modulator K-877 in db/db mice

T2 - A role of diacylglycerol-protein kinase C-NAD(P)H oxidase pathway

AU - Maki, Toshinobu

AU - Maeda, Yasutaka

AU - Sonoda, Noriyuki

AU - Makimura, Hiroaki

AU - Kimura, Shinichiro

AU - Maeno, Sayaka

AU - Takayanagi, Ryoichi

AU - Inoguchi, Toyoshi

PY - 2017/6/1

Y1 - 2017/6/1

N2 - 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 (0.5 mg/kg/day) was administered to db/db mice for 2 or 12 weeks. 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.

AB - 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 (0.5 mg/kg/day) was administered to db/db mice for 2 or 12 weeks. 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.

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U2 - 10.1016/j.metabol.2017.02.013

DO - 10.1016/j.metabol.2017.02.013

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JO - Metabolism: Clinical and Experimental

JF - Metabolism: Clinical and Experimental

SN - 0026-0495

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