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 mitogenactivated 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 (450mg/dl) for 72 hrs significantly increased MAP kinase activity as compared to normal glucose level (100mg/dl). This increase was completely blocked by the treatment of pitavastatin (5x10-7M) as well as a NAD(P)H oxidase inhibitor (diphenylene iodonium, 10-5M) 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.
Keywords: diabetes, nephropathy, map kinase, nad(p)h oxidase, mesangial cell, oxidative stress
Medicinal Chemistry
Title: Statin Attenuates High Glucose-Induced and Angiotensin II-Induced MAP Kinase Activity Through Inhibition of NAD(P)H Oxidase Activity in Cultured Mesangial Cells
Volume: 1 Issue: 5
Author(s): H. Y. Yu, T. Inoguchi, M. Nakayama, H. Tsubouchi, N. Sato, N. Sonoda, S. Sasaki, K. Kobayashi and H. Nawata
Affiliation:
Keywords: diabetes, nephropathy, map kinase, nad(p)h oxidase, mesangial cell, oxidative stress
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 mitogenactivated 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 (450mg/dl) for 72 hrs significantly increased MAP kinase activity as compared to normal glucose level (100mg/dl). This increase was completely blocked by the treatment of pitavastatin (5x10-7M) as well as a NAD(P)H oxidase inhibitor (diphenylene iodonium, 10-5M) 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.
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Yu Y. H., Inoguchi T., Nakayama M., Tsubouchi H., Sato N., Sonoda N., Sasaki S., Kobayashi K. and 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, Medicinal Chemistry 2005; 1 (5) . https://dx.doi.org/10.2174/1573406054864052
DOI https://dx.doi.org/10.2174/1573406054864052 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
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