SIRT3 inhibited the formation of calcium oxalate‐induced kidney stones through regulating NRF2/HO‐1 signaling pathway

摘要

Abstract Oxidative stress is important for the calcium oxalate (CaOx)‐induced kidney stone formation. Sirtuin 3 (SIRT3) plays an essential role in the amelioration of oxidative damages. This study aims to explore the effect of SIRT3 on the formation of CaOx‐induced kidney stones and the underlying mechanism. SIRT3 expression in renal tissues was detected by immunohistochemistry. Apoptosis in renal tissues was examined by TUNEL staining. Crystal‐cell adherence and cell apoptosis in HK‐2 cells were assessed by analyzing Ca 2+ concentration and by the flow cytometry analysis, respectively. Protein expression of SIRT3, nuclear factor erythroid 2‐related factor (NRF2), heme oxygenase‐1 (HO‐1), and Bax in renal tissues or HK‐2 cells was examined by Western blot analysis. Renal pathological changes and the adhesion of CaOx crystals in the kidneys were examined by hematoxylin‐eosin and von Kossa staining, respectively. Human kidneys with stones showed enhanced renal apoptosis, downregulated SIRT3 expression, and upregulated NRF2/HO‐1 expression, compared with the controls. Furthermore, SIRT3 overexpression inhibited the CaOx‐induced promotion of crystal‐cell adherence and cell apoptosis in human proximal tubular cell line HK‐2 cells, which was reversed by the NRF2 knockdown. Moreover, our in vivo assay further confirmed that SIRT3 overexpression alleviated the glyoxylate administration‐induced renal damage, renal apoptosis, and crystals deposition in the kidneys from the stone model mice, which was also associated with its activation of the NRF2/HO‐1 pathway. Our findings support the notion that overexpression of SIRT3 may inhibit the formation of CaOx‐induced kidney stones, at least in part, through regulating the NRF2/HO‐1 signaling pathway.