SIRT2 Regulates LPS-Induced Renal Tubular CXCL2 and CCL2 Expression

Sirtuin2 ( SIRT2), a NAD + -dependent histone deacetylase, is involved in carcinogenesis and genomic instabilityand modulates proinflammatory immune responses. However, its role in renal inflammatory injury has not been demonstrated. In this study, we explored the expression patterns of CXCL2and CCL2in kidney tissue from Sirt2−/− and Sirt2+/+ mice and in mouse proximal tubular epithelial (MPT) cells. CXCL2and CCL2were significantly downregulated at both the mRNA and the protein levels in kidneys of LPS-treated Sirt2−/− mice compared with those of LPS-treated Sirt2+/+ mice. Furthermore, SIRT2deficiency ameliorated LPS-induced infiltration of neutrophils and macrophages, acute tubular injury, and decrease of renal function. Supporting these observations, CXCL2and CCL2expression levels were lower in MPT cells treated with SIRT2-siRNA than in cells treated with control-siRNA, and adenovirus-mediated overexpression of SIRT2in MPT cells significantly increased the LPS-induced expression of CXCL2and CCL2at the mRNA and protein levels. In addition, SIRT2interacted with mitogen-activated protein kinase ( MAPK) phosphatase-1 (MKP-1), and SIRT2-knockdown increased the acetylation of MKP-1 and suppressed the phosphorylation of p38 MAPK and c-Jun N-terminal kinasein LPS-treated MPT cells. SIRT2also regulated p65 binding to the promoters of CXCL2and CCL2. Taken together, these findings indicate that SIRT2is associated with expression of renal CXCL2and CCL2and that regulation of SIRT2might be an important therapeutic target for renal inflammatory injury.