期刊
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
卷 25, 期 2, 页码 1012-1023出版社
WILEY
DOI: 10.1111/jcmm.16165
关键词
AMPK; diabetes nephropathy; mitochondria; NADPH oxidases 4; podocyte injury; reactive oxygen species; Salvianolate
资金
- Science Foundation of China [81700630]
- National Programon Key Research Project [2016YFC1305500]
- Shanghai Key Laboratory of Kidney Disease and Blood Purification [14DZ2260200]
In this study, the effects of Salvianolate on diabetic nephropathy were investigated, showing that Salvianolate attenuated albuminuria, reduced podocyte loss, and restored podocyte loss in diabetic kidneys. Moreover, Salvianolate blocked HG-induced mitochondrial NOX4 derived superoxide generation in human podocytes, ameliorating podocyte apoptosis.
Podocyte injury is associated with albuminuria and the progression of diabetic nephropathy (DN). NADPH oxidase 4 (NOX4) is the main source of reactive oxygen species (ROS) in the kidney and NOX4 is up-regulated in podocytes in response to high glucose. In the present study, the effects of Salvianolate on DN and its underlying mechanisms were investigated in diabetic db/db mice and human podocytes. We confirmed that the Salvianolate administration exhibited similar beneficial effects as the NOX1/NOX4 inhibitor GKT137831 treated diabetic mice, as reflected by attenuated albuminuria, reduced podocyte loss and mesangial matrix accumulation. We further observed that Salvianolate attenuated the increase of Nox4 protein, NOX4-based NADPH oxidase activity and restored podocyte loss in the diabetic kidney. In human podocytes, NOX4 was predominantly localized to mitochondria and Sal B treatment blocked HG-induced mitochondrial NOX4 derived superoxide generation and thereby ameliorating podocyte apoptosis, which can be abrogated by AMPK knockdown. Therefore, our results suggest that Sal B possesses the reno-protective capabilities in part through AMPK-mediated control of NOX4 expression. Taken together, our results identify that Salvianolate could prevent glucose-induced oxidative podocyte injury through modulation of NOX4 activity in DN and have a novel therapeutic potential for DN.
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