Obstructive nephropathy in the mouse: progressive fibrosis correlates with tubulointerstitial chemokine expression and accumulation of CC chemokine receptor 2- and 5-positive leukocytes.
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.
Vielhauer
Volker
V
Nephrologisches Zentrum, Medizinische Poliklinik, Ludwig-Maximilians-University, Munich, Germany.
Anders
Hans-Joachim
HJ
Nephrologisches Zentrum, Medizinische Poliklinik, Ludwig-Maximilians-University, Munich, Germany.
Mack
Matthias
M
Nephrologisches Zentrum, Medizinische Poliklinik, Ludwig-Maximilians-University, Munich, Germany.
Cihak
Josef
J
Department of Animal Physiology, Ludwig-Maximilians-University, Munich, Germany.
Strutz
Frank
F
Department of Nephrology and Rheumatology, University of Göttingen, Göttingen, Germany.
Stangassinger
Manfred
M
Department of Animal Physiology, Ludwig-Maximilians-University, Munich, Germany.
Luckow
Bruno
B
Nephrologisches Zentrum, Medizinische Poliklinik, Ludwig-Maximilians-University, Munich, Germany.
Gröne
Hermann-Josef
HJ
Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
Schlöndorff
Detlef
D
Nephrologisches Zentrum, Medizinische Poliklinik, Ludwig-Maximilians-University, Munich, Germany.
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
D019742:Chemokines, CC; D012333:RNA, Messenger; D019707:Receptors, Chemokine