SIRT2 regulates LPS-induced renal tubular CXCL2 and CCL2 expression

Abstract

Sirtuin 2 (SIRT2), aNAD+-dependent histone deacetylase, is involvedin carcinogenesis and genomic instability and modulates proinflammatory immune responses. However, its role in renal inflammatory injury has not been demonstrated. In this study, we explored the expression patterns of CXCL2 and CCL2 in kidney tissue from Sirt22/2 and Sirt2+/+ mice and in mouse proximal tubular epithelial (MPT) cells. CXCL2 and CCL2 were significantly downregulated at both themRNAand the protein levels in kidneys of LPS-treated Sirt22/2 mice compared with those of LPS-treated Sirt2+/+ mice. Furthermore, SIRT2 deficiency ameliorated LPS-induced infiltration of neutrophils and macrophages, acute tubular injury, and decrease of renal function. Supporting these observations, CXCL2 and CCL2 expression levels were lower in MPT cells treated with SIRT2-siRNA than in cells treated with control-siRNA, and adenovirus-mediated overexpression of SIRT2 in MPT cells significantly increased the LPS-induced expression of CXCL2 and CCL2 at the mRNA and protein levels. In addition, SIRT2 interacted 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 kinase in LPS-treated MPT cells. SIRT2 also regulated p65 binding to the promoters of CXCL2 and CCL2. Taken together, these findings indicate that SIRT2 is associated with expression of renal CXCL2 and CCL2 and that regulation of SIRT2might be an important therapeutic target for renal inflammatory injury.