title: CCR5 deficiency increased susceptibility to lipopolysaccharide-induced acute renal injury.
abstract: C-C chemokine receptor 5 (CCR5) regulates leukocyte chemotaxis and activation, and its deficiency exacerbates development of nephritis. Therefore, we investigated the role of CCR5 during lipopolysaccharide (LPS)-induced acute kidney injury. CCR5-deficient (CCR5-/-) and wild-type (CCR5+/+) mice, both aged about 10 months, had acute renal injury induced by intraperitoneal injection of LPS (10 mg/kg). Compared with CCR5+/+ mice, CCR5-/- mice showed increased mortality and renal injury, including elevated creatinine and blood urea nitrogen levels, following LPS challenge. Compared to CCR5+/+ mice, CCR5-/- mice also exhibited greater increases in the serum concentrations of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β following LPS challenge. Furthermore, infiltration of macrophages and neutrophils, expression of intracellular adhesion molecule (ICAM)-1, and the number of apoptotic cells were more greatly increased by LPS treatment in CCR5-/- mice than in CCR5+/+ mice. The concentrations of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β were also significantly increased in the kidney of CCR5-/- mice after LPS challenge. Moreover, primary kidney cells from CCR5-/- mice showed greater increases in TNF-α production and p38 MAP kinase activation following treatment with LPS compared with that observed in the cells from CCR5+/+ mice. LPS-induced TNF-α production and apoptosis in the primary kidney cells from CCR5-/- mice were inhibited by treatment with p38 MAP kinase inhibitor. These results suggest that CCR5 deficiency increased the production of TNF-α following LPS treatment through increased activation of the p38 pathway in the kidney, resulting in renal apoptosis and leukocyte infiltration and led to exacerbation of LPS-induced acute kidney injury.
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31 Osongsaengmyeong 1-ro, Osong-eup, Heungduk-gu, Cheongju, Chungbuk, 361-951, Republic of Korea.
authors.forename: Dong Hun
authors.initials: DH
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31 Osongsaengmyeong 1-ro, Osong-eup, Heungduk-gu, Cheongju, Chungbuk, 361-951, Republic of Korea.
authors.forename: Mi Hee
authors.initials: MH
authors.lastname: Park
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31 Osongsaengmyeong 1-ro, Osong-eup, Heungduk-gu, Cheongju, Chungbuk, 361-951, Republic of Korea.
authors.forename: Chul Ju
authors.initials: CJ
authors.lastname: Hwang
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31 Osongsaengmyeong 1-ro, Osong-eup, Heungduk-gu, Cheongju, Chungbuk, 361-951, Republic of Korea.
authors.forename: Jae Yeon
authors.initials: JY
authors.lastname: Hwang
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31 Osongsaengmyeong 1-ro, Osong-eup, Heungduk-gu, Cheongju, Chungbuk, 361-951, Republic of Korea.
authors.forename: Hae Suk
authors.initials: HS
authors.lastname: Yoon
authors.affiliation: Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, 1, Hwayang-dong, Gwangjin-gu, Seoul, 143-701, Republic of Korea. ydy4218@konkuk.ac.kr.
authors.forename: Do Young
authors.initials: DY
authors.lastname: Yoon
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31 Osongsaengmyeong 1-ro, Osong-eup, Heungduk-gu, Cheongju, Chungbuk, 361-951, Republic of Korea. jinthong@chungbuk.ac.kr.
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000097:blood; D001806:Blood Urea Nitrogen; D002478:Cells, Cultured; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D018836:Inflammation Mediators / Q000097:blood; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects; D010641:Phenotype; D019713:Receptors, CCR5 / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D015415:Biomarkers; C000592874:CCR5 protein, mouse; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D019713:Receptors, CCR5; D014409:Tumor Necrosis Factor-alpha; D003404:Creatinine; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Acute kidney injury; CCR5; Cytokine; MAP kinase