Abstract

NADPH oxidase (NOX) has been reported to contribute to glomerulosclerosis induced by hyperhomocysteinemia (hHcys). In the present study, we used a mouse model lacking gp91phox (gp91−/−), a membrane subunit of NOX, to test whether the pathogenic role of NOX is associated with podocytes injury induced by hHcys. gp91−/− and wild‐type mice (gp91+/+) were fed on folate‐free (FF) or normal chow for 6 weeks. HPLC analysis showed that both strains of mice had higher plasma homocysteine levels on FF diet compared to the mice on normal chow (9.86 ± 1.06 vs. 4.98 ± 0.52 μM in gp91−/− mice and 10.53± 1.27 vs. 5.05 ± 0.68 µM in gp91+/+ mice). ESR analysis showed that hHcys failed to markedly increase NOX‐dependent superoxide production in kidneys from gp91−/− mice compared with gp91+/+ mice. Glomerular sclerosis index was markedly lower in gp91−/− than in gp91+/+ mice on FF diet. RT‐PCR showed that hHcys significantly decreased nephrin mRNA expression in gp91+/+ mice but not in gp91−/− mice. Correspondingly, desmin mRNA expression was less elevated in gp91−/− mice on FF diet. Immunohistochemistry demonstrated decreased nephrin and increased desmin staining in gp91+/+ mice on FF diet, rather than in gp91−/− mice. Our results suggest that knock‐out of gp91phox leads to a substantial reduction of local oxidative stress in glomeruli, which protects podocytes from hHcys‐induced injury (supported by NIH grants DK54927 and HL075316).

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