title: CCR2 antagonism improves insulin resistance, lipid metabolism, and diabetic nephropathy in type 2 diabetic mice.
abstract: Chemokine ligand 2 (CCL2) binds to its receptor C-C chemokine receptor 2 (CCR2), initiating tissue inflammation, and recent studies have suggested a beneficial effect of a blockade of this pathway in diabetic nephropathy. To investigate the mechanism of protection, we studied the effect of RS504393, a CCR2 antagonist, on insulin resistance and diabetic nephropathy in db/db mice. Administering this antagonist improved insulin resistance as confirmed by various biomarkers, including homeostasis model assessment index levels, plasma insulin levels, and lipid abnormalities. Mice treated with the antagonist had a significant decrease in epididymal fat mass as well as phenotypic changes of adipocytes into small differentiated forms with decreased CCL2 expression and lipid hydroperoxide levels. In addition, treatment with the CCR2 antagonist markedly decreased urinary albumin excretion, mesangial expansion, and suppressed profibrotic and proinflammatory cytokine synthesis. Furthermore, the CCR2 antagonist improved lipid metabolism, lipid hydroperoxide, cholesterol, and triglyceride contents of the kidney, and decreased urinary 8-isoprostane levels. Hence, our findings suggest that CCR2 antagonists can improve insulin resistance by modulation of the adipose tissue and restore renal function through both metabolic and anti-fibrotic effects in type 2 diabetic mice.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Korea University, Ansan City, Korea.
authors.forename: Young Sun
authors.initials: YS
authors.lastname: Kang
authors.forename: Mi Hwa
authors.initials: MH
authors.lastname: Lee
authors.forename: Hye Kyoung
authors.initials: HK
authors.lastname: Song
authors.forename: Gang Jee
authors.initials: GJ
authors.lastname: Ko
authors.forename: Oh Sung
authors.initials: OS
authors.lastname: Kwon
authors.forename: Tae Kyung
authors.initials: TK
authors.lastname: Lim
authors.forename: Sung Hwan
authors.initials: SH
authors.lastname: Kim
authors.forename: Sang Youb
authors.initials: SY
authors.lastname: Han
authors.forename: Kum Hyun
authors.initials: KH
authors.lastname: Han
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Lee
authors.forename: Jee Young
authors.initials: JY
authors.lastname: Han
authors.forename: Hyoung Kyu
authors.initials: HK
authors.lastname: Kim
authors.forename: Dae Ryong
authors.initials: DR
authors.lastname: Cha
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D052242:Adiponectin / Q000097:blood; D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000419:Albuminuria / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D005355:Fibrosis; D005786:Gene Expression Regulation; D006442:Glycated Hemoglobin / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors
chemical_list: D052242:Adiponectin; D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D001786:Blood Glucose; D016207:Cytokines; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D018836:Inflammation Mediators; D007328:Insulin; D054390:Receptors, CCR2; C499919:Adipoq protein, mouse; C515335:Ccr2 protein, mouse