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1 Division of Nephrology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan; Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine and Dentistry, Okayama, Okayama, Japan
2 Division of Nephrology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Okayama, Japan
3 Department of Physiology, Kawasaki Medical School, Kurashiki, Okayama, Japan
4 Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine and Dentistry, Okayama, Okayama, Japan
* To whom correspondence should be addressed. E-mail: satoh-minoru{at}mx1.tiki.ne.jp.
Increased production of reactive oxygen species (ROS) in diabetes may be a common pathway linking diverse pathogenic mechanisms of diabetic vascular complications including nephropathy. Assessment of oxidative stress production pathway is therefore important for the prediction and prevention of diabetic complications. However, the ROS production mechanisms remain unclear in diabetic glomeruli. To identify the source and determine the mechanisms of ROS production in the diabetic kidney, diabetes was induced with streptozotocin in rats. After six weeks, glomerular ROS production had increased in the STZ rat kidney, as assessed by dihydroethidium-derived chemiluminescence. ROS production was increased by the addition of NADH or L-arginine and was partially reduced by the addition of diphenylene iodonium or N(G)-nitro-L-arginine methyl ester, identifying NAD(P)H oxidase and NO synthase (NOS) as ROS sources. The mRNA and protein expression of endothelial NOS (eNOS), as measured by real-time RT-PCR and western blotting, increased significantly (mRNA level; 1.3-folds, protein level; 1.8-folds). However, the dimeric form of eNOS was decreased in diabetic glomeruli, as measured by lowtemperature SDS-PAGE. Renal ROS and NO production by uncoupled NOS were imaged by confocal laser microscopy after renal perfusion of 2',7'-dichlorofluorescin diacetate (a ROS marker) and diaminorhodamine-4M AM (a NO marker) with L-arginine. Accelerated ROS production and diminished bioavailable NO caused by NOS uncoupling were noted in the diabetic kidney. Administration of tetrahydrobiopterin (BH4), a co-factor for eNOS, reversed the decreased dimeric form of eNOS and glomerular NO production. Our results indicate that NAD(P)H oxidase and uncoupling of eNOS contribute to glomerular ROS production, mediated by the loss of BH4 availability. These mechanisms are potential key targets for therapeutic interventions.
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