title: Obstructive nephropathy in the mouse: progressive fibrosis correlates with tubulointerstitial chemokine expression and accumulation of CC chemokine receptor 2- and 5-positive leukocytes.
abstract: The infiltration of leukocytes plays a major role in mediating tubulointerstitial inflammation and fibrosis in chronic renal disease. CC chemokines participate in leukocyte migration and infiltration into inflamed renal tissue. Because CC chemokine-directed leukocyte migration is mediated by target cell expression of a group of CC chemokine receptors, this study examined the expression of CC chemokines and their receptors during initiation of tubulointerstitial fibrosis after unilateral ureteral obstruction in C57BL/6 mice. Obstructed kidneys developed hydronephrosis, tubular cell damage, interstitial inflammation, and fibrosis. From days 2 to 10, a progressive interstitial influx of F4/80+ macrophages and CD3+ lymphocytes occurred (macrophages, 4-fold; lymphocytes, 20-fold at day 10, compared with contralateral control kidneys). In parallel, the number of activated fibroblast-specific protein 1+ fibroblasts and interstitial collagen IV accumulation increased from days 2 to 10. The mRNA expression of CC chemokines (predominantly monocyte chemoattractant protein-1 [MCP-1]/CCL2, RANTES/CCL5) and their receptors CCR1, CCR2, CCR5 increased progressively from days 2 to 10. By in situ hybridization, a prominent interstitial mRNA expression of MCP-1 and RANTES and their receptors CCR2 and CCR5 localized to interstitial mononuclear cell infiltrates. MCP-1 and RANTES expression was also seen in tubular epithelial cells. Fluorescence-activated cell sorter analysis of single-cell suspensions from obstructed kidneys revealed a prominent expression of CCR2 and CCR5 by infiltrating macrophages, whereas most lymphocytes expressed CCR5 only. These data demonstrate an increased expression of MCP-1/CCL2 and RANTES/CCL5 at sites of tubulointerstitial damage and progressive fibrosis during unilateral ureteral obstruction that correlates with simultaneous accumulation of interstitial macrophages and T lymphocytes expressing the respective surface receptors CCR2 and CCR5. The chemokine receptor-mediated leukocyte influx into the tubulointerstitium could offer a new potential target for therapeutic intervention in progressive renal tubulointerstitial fibrosis.
authors.affiliation: Nephrologisches Zentrum, Medizinische Poliklinik, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Vielhauer
authors.affiliation: Nephrologisches Zentrum, Medizinische Poliklinik, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Anders
authors.affiliation: Nephrologisches Zentrum, Medizinische Poliklinik, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mack
authors.affiliation: Department of Animal Physiology, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Cihak
authors.affiliation: Department of Nephrology and Rheumatology, University of Göttingen, Göttingen, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Strutz
authors.affiliation: Department of Animal Physiology, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Stangassinger
authors.affiliation: Nephrologisches Zentrum, Medizinische Poliklinik, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Bruno
authors.initials: B
authors.lastname: Luckow
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.affiliation: Nephrologisches Zentrum, Medizinische Poliklinik, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Detlef
authors.initials: D
authors.lastname: Schlöndorff
mesh_terms: D000818:Animals; D019742:Chemokines, CC / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D005434:Flow Cytometry; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D007962:Leukocytes; D051379:Mice; D008810:Mice, Inbred C57BL; D009395:Nephritis, Interstitial / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism*; D014517:Ureteral Obstruction / Q000378:metabolism* / Q000473:pathology
chemical_list: D019742:Chemokines, CC; D012333:RNA, Messenger; D019707:Receptors, Chemokine