Statin attenuates high glucose-induced and angiotensin II-induced MAP kinase activity through inhibition of NAD(P)H oxidase activity in cultured mesangial cells.

H. Y. Yu, T. Inoguchi, M. Nakayama, H. Tsubouchi, N. Sato, N. Sonoda, S. Sasaki, K. Kobayashi, H. Nawata

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Abstract

An increased oxidative stress may contribute to the development of diabetic nephropathy. We have recently reported that high glucose level stimulated superoxide production through protein kinase C (PKC)-dependent activation of NAD(P)H oxidase in cultured vascular cells. Here we show that 3-hydroxy-3-methylglutaryl CoA reductase inhibitor (statin) attenuates both high glucose level-induced and angiotensin II (Ang II)-induced activation of p42/44 mitogen-activated kinase (MAP kinase) in cultured human mesangial cells through inhibition of NAD(P)H oxidase activity. The intracellular oxidative stress in cultured mesangial cells was evaluated by electron spin resonance (ESR) measurement. MAP kinase activity was evaluated by western blot analysis using anti phospho-specific MAP kinase antibody and anti-ERK-1 antibody. Exposure of the cells to high glucose level (450 mg/dl) for 72 hrs significantly increased MAP kinase activity as compared to normal glucose level (100 mg/dl). This increase was completely blocked by the treatment of pitavastatin (5x10(-7) M) as well as a NAD(P)H oxidase inhibitor (diphenylene iodonium, 10(-5) M) in parallel with the attenuation of oxidative stress. Ang II-induced activation of MAP kinase was also completely blocked by pitavastatin as well as a diphenylene iodonium in parallel with the attenuation of oxidative stress. In conclusion, pitavastatin attenuated high glucose-induced and Ang II- induced MAP kinase activity in mesangial cells through inhibition of NAD(P)H oxidase. Thus, statins may have a potential as a therapeutic tool for early diabetic nephropathy.

Original languageEnglish
Pages (from-to)461-466
Number of pages6
JournalMedicinal chemistry
Volume1
Issue number5
DOIs
Publication statusPublished - Sep 2005

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Hydroxymethylglutaryl-CoA Reductase Inhibitors
Mesangial Cells
NADPH Oxidase
Angiotensin II
Cultured Cells
Phosphotransferases
Glucose
Oxidative Stress
Diabetic Nephropathies
Hydroxymethylglutaryl CoA Reductases
Mitogen-Activated Protein Kinase Kinases
Electron Spin Resonance Spectroscopy
Mitogens
Superoxides
Protein Kinase C
Blood Vessels
Anti-Idiotypic Antibodies
Western Blotting
Antibodies
pitavastatin

All Science Journal Classification (ASJC) codes

  • Drug Discovery

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Statin attenuates high glucose-induced and angiotensin II-induced MAP kinase activity through inhibition of NAD(P)H oxidase activity in cultured mesangial cells. / Yu, H. Y.; Inoguchi, T.; Nakayama, M.; Tsubouchi, H.; Sato, N.; Sonoda, N.; Sasaki, S.; Kobayashi, K.; Nawata, H.

In: Medicinal chemistry, Vol. 1, No. 5, 09.2005, p. 461-466.

Research output: Contribution to journalArticle

Yu, H. Y. ; Inoguchi, T. ; Nakayama, M. ; Tsubouchi, H. ; Sato, N. ; Sonoda, N. ; Sasaki, S. ; Kobayashi, K. ; Nawata, H. / Statin attenuates high glucose-induced and angiotensin II-induced MAP kinase activity through inhibition of NAD(P)H oxidase activity in cultured mesangial cells. In: Medicinal chemistry. 2005 ; Vol. 1, No. 5. pp. 461-466.
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