MO003: Upregulation of NADH/NADPH Oxidase 4 by Angiotensin II Induces Podocyte Apoptosis
Nephrology Dialysis Transplantation(2022)
Abstract
Abstract BACKGROUND AND AIMS Oxidative stress induced by non-hemodynamic effects of angiotensin II in podocytes participates in the development of glomerular injury and proteinuria. We studied the pathophysiologic roles of oxidative stress in angiotensin II-induced podocyte apoptosis. METHOD Mouse podocytes were incubated in media containing various concentrations of angiotensin II at different incubation times and transfected by Nox4 or AT1R siRNAs or negative control scrambled siRNA for 24 h. The changes of podocyte oxidative stress and apoptosis were observed by confocal imaging, western blotting, real-time PCR, FACS and TUNEL assays according to the presence of angiotensin II. RESULTS Angiotensin II increased the generation of mitochondrial superoxide anions and reactive oxygen species levels but suppressed superoxide dismutase activity that was reversed by probucol, an antioxidant. Angiotensin II also increased NADH/NADPH oxidase 4 protein and expression in a transcriptional mechanism that was also reversed by probucol. In addition, the suppression of NADH/NADPH oxidase 4 by siRNA reduced the oxidative stress induced by angiotensin II. Furthermore, angiotensin II promoted podocyte apoptosis that was reduced significantly by probucol and NADH/NADPH oxidase 4 siRNA, and also recovered by angiotensin II type 1 receptor siRNA. In sum, angiotensin II induced podocyte oxidative stress and apoptosis through NADH/NADPH oxidase 4 and angiotensin II type 1 receptor. CONCLUSION These findings suggest that angiotensin II promotes podocyte mitochondrial oxidative stress, resulting in apoptosis via the upregulation of NADH/NADPH oxidase 4 and angiotensin II type 1 receptor, which could be prevented by NADH/NADPH oxidase 4 inhibition and/or antagonizing angiotensin II type 1 receptor as well as antioxidants.
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Key words
nadh/nadph oxidase,apoptosis,angiotensin ii
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