Sirtuin 2 exacerbates renal tubule injury and inflammation in diabetic mice via deacetylation of c-Jun/c-Fos.

Abstract

Diabetic nephropathy (DN) is a serious complication of diabetes, and inflammation plays a crucial role. Sirtuin 2 (SIRT2), a NAD+-dependent deacetylase, which is involved in the regulation of cell metabolism, proliferation and longevity through deacetylation. Our previous research showed a positive correlation between urinary SIRT2 levels and renal injury markers in DN patients. Therefore, this study explored the specific role of SIRT2 in DN and its regulatory relationship with inflammatory response. Increased expression of SIRT2 was observed in kidney tissues of DN mice and in HK2 cells induced by HG/PA. SIRT2 knockout mice alleviated microalbuminuria, inflammatory responses, and kidney damage induced by HFD/STZ. In HK2 cells, reducing SIRT2 expression or inhibiting its acetylase activity alleviated the inflammatory response induced by HG/PA, whereas overexpression of SIRT2 exacerbated this response. Further investigation revealed that SIRT2 directly interacts with c-Jun/c-Fos, promoting their deacetylation. And inhibitors of c-Jun/c-Fos partially reversed the upregulation of inflammatory factors caused by SIRT2 overexpression. Meanwhile, disrupting SIRT2 reduced the binding activity between AP-1 and the MCP-1 promoter, while overexpressing SIRT2 further increased their binding activity in HK2 cells. Interestingly, SIRT2 increased its phosphorylation while deacetylating c-Jun, leading to nuclear accumulation of p-c-Jun. In conclusion, SIRT2 knockout can alleviate kidney injury and inflammatory response in HFD/STZ mice. The mechanism is related to the increased acetylation of c-Jun/c-Fos in renal tubular epithelial cells, accompanied by crosstalk between c-Jun phosphorylation and acetylation. Blocking SIRT2 could therefore be a potential therapeutic target for DN.