Abstract
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.
Highlights
Diabetic nephropathy (DN) is the leading cause of the end-stage renal disease (ESRD), accounting for a high burden of morbidity and mortality.[1]
Our results indicated that Salvianolic acid B (Sal B) administration could inhibit the induction of NADPH oxidase 4 (NOX4) and NADPH activity by high glucose (HG) and prevent the subsequent enhanced reactive oxygen species (ROS) production, thereby attenuating podocyte injury, which can be abrogated by AMPK knockdown
Diabetic nephropathy (DN) is the leading cause of ESRD as it affects as much as one-third of diabetics
Summary
Diabetic nephropathy (DN) is the leading cause of the end-stage renal disease (ESRD), accounting for a high burden of morbidity and mortality.[1]. Our team has demonstrated previously that Sal B exerted anti-oxidative effects to protect renal tubular cells from iodinated contrast media-induced acute kidney injury (AKI).[19] Based on these clues, it is reasonable to hypothesize that SAL inhibited high glucose-induced NOX4-based ROS generation in podocytes through AMPK-mediated control of Nox[4] expression, thereby ameliorating podocyte injury in DN. There are no reports on the role of SAL against podocyte injury and progression of DN Based on these findings, here we attempt to address (a) The therapeutic effects of SAL in db/db diabetic mice; (b) the role of Sal B on NOX4 activity, NOX4-derived mitochondrial ROS production and apoptosis of podocytes under high glucose; and (c) whether AMPK is required for Sal B to attenuate NOX4-induced podocyte injury in DN. Key findings in vivo studies were confirmed in vitro using human podocytes
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