Enhanced hydrogen peroxide-dependent renin and pro-renin release in juxtaglomerular cells from diabetic mice: Role of NOX1

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A large fraction of patients with diabetes mellitus develop diabetic nephropathy and are hypertensive. The Akita mice is one of the few mouse models of diabetes mellitus with features of the human disease including hypertension and kidney damage. Previous data showed increased levels of reactive oxygen species in the kidneys of Akita mice. We found that hydrogen peroxide (H2O2) is a potent stimulus for renin release from the juxtaglomerular (JG) cells in vitro and in vivo. Plasma pro-renin levels are elevated in diabetic patients and thought to contribute to hypertension and renal damage. Thus, we hypothesized that H2O2 levels are higher in JG cells from Akita mice leading to increased renin and pro-renin release in diabetes. We measured H2O2 by transducing primary cultures of JG cells with the fluorescent protein H2O2sensor Hyper, under control of the renin1 promoter. JG cells isolated from Akita mice had higher baseline levels of H2O2 (C57= 100, Akita=222.5±79%, p<0.05). We also found that pro-renin expression was higher in JG cells from Akita by 79±21% (p<0.05). In addition, JG cells from Akita mice have higher pro-renin (n=4; p<0.05) and renin (C57= 100, Akita=219.2±26%; p<0.04, n=6) release to the media when compared to JG cells from C57. Western Blots showed that the NADPH oxidase isoform NOX1 is upregulated in JG cells from Akita mice (C57=100%; Akita=147±10%; n=4; p<0.05), whereas NOX2 or NOX4 were not different. NOX1 co-localized with renin-containing granules in kidney sections analyzed by confocal microscopy (n=4). Silencing NOX1 in JG cells from Akita mice decreased renin release to C57 control levels; (n=6; p<0.01) while silencing NOX4 had no effect (n=6). Expression of Catalase, which scavenges H2O2, was reduced in JG cells from Akita mice (C57=100%; Akita= 36±9.2%; n=4; p<0.05) and overexpression of Catalase in JG cells from Akita decreased baseline renin release by 35±8% (p<0.05). We conclude that renin cells from diabetic Akita mice have higher endogenous H2O2 leading to increased renin and pro-renin release via enhanced NOX1 expression and decreased catalase. Enhanced H2O2-dependent renin release in Akita JG cells could be involved in renal damage and hypertension in diabetes mellitus.



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