title: SIRT2 Regulates LPS-Induced Renal Tubular CXCL2 and CCL2 Expression.
abstract: Sirtuin 2 (SIRT2), a NAD(+)-dependent histone deacetylase, is involved in 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 Sirt2(-/-) and Sirt2(+/+) mice and in mouse proximal tubular epithelial (MPT) cells. CXCL2 and CCL2 were 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, 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 SIRT2 might be an important therapeutic target for renal inflammatory injury.
authors.affiliation: Department of Internal Medicine and.
authors.forename: Yu Jin
authors.initials: YJ
authors.lastname: Jung
authors.affiliation: Department of Internal Medicine and.
authors.forename: Ae Sin
authors.initials: AS
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine and.
authors.forename: Tung
authors.initials: T
authors.lastname: Nguyen-Thanh
authors.affiliation: Department of Internal Medicine and.
authors.forename: Dal
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine and Research Institute of Clinical Medicine of Chonbuk National University-Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Kyung Pyo
authors.initials: KP
authors.lastname: Kang
authors.affiliation: Department of Internal Medicine and Research Institute of Clinical Medicine of Chonbuk National University-Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Sik
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine and Research Institute of Clinical Medicine of Chonbuk National University-Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Sung Kwang
authors.initials: SK
authors.lastname: Park
authors.affiliation: Department of Internal Medicine and Research Institute of Clinical Medicine of Chonbuk National University-Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Republic of Korea kwon@jbnu.ac.kr.
authors.forename: Won
authors.initials: W
authors.lastname: Kim
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics*; D054426:Chemokine CXCL2 / Q000235:genetics*; D004195:Disease Models, Animal; D015536:Down-Regulation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016133:Polymerase Chain Reaction / Q000379:methods; D011897:Random Allocation; D056565:Sirtuin 2 / Q000378:metabolism*
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D008070:Lipopolysaccharides; D020928:Mitogen-Activated Protein Kinases; D056565:Sirtuin 2
keywords: CCL2; CXCL2; SIRT2; mitogen-activated protein kinase (MAPK); phosphatase-1 acetylation