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Free Radic Biol Med. 2010 Apr 15;48(8):1109-17. doi: 10.1016/j.freeradbiomed.2010.01.029. Epub 2010 Jan 29.

Protection of podocytes from hyperhomocysteinemia-induced injury by deletion of the gp91phox gene.

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Department of Pharmacology & Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, USA.


In this study, mice lacking the gp91(phox) gene were used to address the role of NADPH oxidase in hyperhomocysteinemia-induced podocyte injury. It was found that a folate-free diet increased plasma homocysteine levels, but failed to increase O(2)(-) production in the glomeruli from gp91(phox) gene knockout (gp91(-/-)) mice, compared with wild-type (gp91(+/+)) mice. Proteinuria and glomerular damage index (GDI) were significantly lower, whereas the glomerular filtration rate (GFR) was higher in gp91(-/-) than in gp91(+/+) mice when they were on the folate-free diet (urine albumin excretion, 21.23+/-1.88 vs 32.86+/-4.03 microg/24 h; GDI, 1.17+/-0.18 vs 2.59+/-0.49; and GFR, 53.01+/-4.69 vs 40.98+/-1.44 microl/min). Hyperhomocysteinemia-induced decrease in nephrin expression and increase in desmin expression in gp91(+/+) mice were not observed in gp91(-/-) mice. Morphologically, foot process effacement and podocyte loss due to hyperhomocysteinemia were significantly attenuated in gp91(-/-) mice. In in vitro studies of podocytes, homocysteine was found to increase gp91(phox) expression and O2(*)(-) generation, which was substantially inhibited by gp91(phox) siRNA. Functionally, homocysteine-induced decrease in vascular endothelial growth factor-A production was abolished by gp91(phox) siRNA or diphenyleneiodonium, a NADPH oxidase inhibitor. These results suggest that the functional integrity of NADPH oxidase is essential for hyperhomocysteinemia-induced podocyte injury and glomerulosclerosis.

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