Sulfiredoxin-1 alleviates high glucose-induced podocyte injury though promoting Nrf2/ARE signaling via inactivation of GSK-3β.

Hyperglycemia-induced podocyte injury plays a vital role in the development of diabetic nephropathy. Sulfiredoxin-1 (Srxn1) is emerging as a cytoprotective protein that protects from various insults in a wide range of cell types. However, whether Srxn1 is involved in regulating hyperglycemia-induced podocyte injury and participates in diabetic nephropathy remains unknown. In the present study, we aimed to explore the potential role of Srxn1 in regulating high glucose (HG)-induced apoptosis and oxidative stress of podocytes in vitro. Results demonstrated that Srxn1 was induced in HG-stimulated podocytes. The depletion of Srxn1 by Srxn1 siRNA-mediated gene silencing significantly exacerbated HG-induced apoptosis and the production of reactive oxygen species while Srxn1 overexpression attenuated HG-induced apoptosis and production. In-depth molecular mechanism research revealed that Srxn1 overexpression promoted the nuclear expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and reinforced antioxidant response element (ARE)-mediated transcription activity. Moreover, results confirmed that Srxn1 increased the activation of Nrf2/ARE signaling associated with inactivating glycogen synthase kinase (GSK)-3β. Notably, the inhibition of GSK-3β significantly reversed Srxn1 silencing-induced adverse effects in HG-treated cells, while the knockdown of Nrf2 abrogated the Srxn1-mediated protective effect against HG-induced podocyte injury. Taken together, our results demonstrated that Srxn1 protects podocytes from HG-induced injury by promoting the activation of Nrf2/ARE signaling associated with inactivating GSK-3β, indicating a potential role of Srxn1 in diabetic nephropathy. Our study suggests that Srxn1 may serve as a potential target for kidney protection.

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