Journal
JOURNAL OF PINEAL RESEARCH
Volume 51, Issue 3, Pages 338-344Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1600-079X.2011.00894.x
Keywords
diabetic nephropathy; glomerular filtration rate; hyperfiltration; melatonin; mitochondria; mitochondrial complex I and III; reactive oxygen species
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Funding
- NIH [R01 HL075011, R01 DK078971]
- American Heart Association
- National Natural Science Foundation of China [30800409, 30700812, 30900673, SJ08-ZT10]
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We have previously demonstrated that melatonin, at pharmacological concentrations, causes rapid reactive oxygen species (ROS) generation at the antimycin-A sensitive site of mitochondrial complex III (MC-3). In the current work, we used this melatonin response to investigate the role of mitochondrial dysfunction in the development of diabetic nephropathy. We find that the development of diabetic nephropathy, as indicated by hyperfiltration and histopathological lesions in the kidney of db/db mice, is associated with diminished melatonin-induced ROS generation and MC-3 activity, indicating impaired MC-3 at the antimycin-A site. The MC-3 protein level in the renal mitochondria was equivalent in db/db and the nondiabetic db/m mice, whereas mitochondrial complex I (MC-1) protein was dramatically upregulated in the db/db mice. This differential regulation in mitochondrial complexes may alter the equilibrium of the electron transport in renal mitochondria and contribute to ROS overproduction. The study provides one mechanism of enhanced oxidative stress that may be involved in the pathogenesis of diabetic nephropathy in db/db mice.
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