title: Blockade of CCR2 reduces macrophage influx and development of chronic renal damage in murine renovascular hypertension.
abstract: Renovascular hypertension (RVH) is a common cause of both cardiovascular and renal morbidity and mortality. In renal artery stenosis (RAS), atrophy in the stenotic kidney is associated with an influx of macrophages and other mononuclear cells. We tested the hypothesis that chemokine receptor 2 (CCR2) inhibition would reduce chronic renal injury by reducing macrophage influx in the stenotic kidney of mice with RAS. We employed a well-established murine model of RVH to define the relationship between macrophage infiltration and development of renal atrophy in the stenotic kidney. To determine the role of chemokine ligand 2 (CCL2)/CCR2 signaling in the development of renal atrophy, mice were treated with the CCR2 inhibitor RS-102895 at the time of RAS surgery and followed for 4 wk. Renal tubular epithelial cells expressed CCL2 by 3 days following surgery, a time at which no significant light microscopic alterations, including interstitial inflammation, were identified. Macrophage influx increased with time following surgery. At 4 wk, the development of severe renal atrophy was accompanied by an influx of inducible nitric oxide synthase (iNOS)+ and CD206+ macrophages that coexpressed F4/80, with a modest increase in macrophages coexpressing arginase 1 and F4/80. The CCR2 inhibitor RS-102895 attenuated renal atrophy and significantly reduced the number of dual-stained F4/80+ iNOS+ and F4/80+ CD206+ but not F4/80+ arginase 1+ macrophages. CCR2 inhibition reduces iNOS+ and CD206+ macrophage accumulation that coexpress F4/80 and renal atrophy in experimental renal artery stenosis. CCR2 blockade may provide a novel therapeutic approach to humans with RVH.
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota;
authors.forename: Sonu
authors.initials: S
authors.lastname: Kashyap
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota;
authors.forename: Gina M
authors.initials: GM
authors.lastname: Warner
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Mayo Medical School, Mayo Clinic, Rochester, Minnesota; and.
authors.forename: Stella P
authors.initials: SP
authors.lastname: Hartono
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota;
authors.forename: Rajendra
authors.initials: R
authors.lastname: Boyilla
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota;
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Knudsen
authors.affiliation: Mayo Medical School, Mayo Clinic, Rochester, Minnesota; and.
authors.forename: Adeel S
authors.initials: AS
authors.lastname: Zubair
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota;
authors.forename: Karen
authors.initials: K
authors.lastname: Lien
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota.
authors.forename: Karl A
authors.initials: KA
authors.lastname: Nath
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Textor
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota.
authors.forename: Lilach O
authors.initials: LO
authors.lastname: Lerman
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota grande.joseph@mayo.edu.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Grande
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001119:Arginase / Q000378:metabolism; D001284:Atrophy; D048588:Benzoxazines / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D019610:Cytoprotection; D004195:Disease Models, Animal; D006978:Hypertension, Renovascular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D037181:Lectins, C-Type / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009395:Nephritis, Interstitial / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D020011:Protective Agents / Q000494:pharmacology*; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D012078:Renal Artery Obstruction / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D000943:Antigens, Differentiation; D048588:Benzoxazines; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D010880:Piperidines; D020011:Protective Agents; C573791:RS 102895; D054390:Receptors, CCR2; D011956:Receptors, Cell Surface; C036763:monocyte-macrophage differentiation antigen; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C544448:Arg1 protein, mouse; D001119:Arginase
keywords: CCL2; CCR2; hypertension; macrophages; parenchymal cells; renal artery stenosis