title: Compartment-specific expression and function of the chemokine IP-10/CXCL10 in a model of renal endothelial microvascular injury.
abstract: The recruitment of inflammatory cells into renal tissue, mainly T cells and monocytes, is a typical feature of various renal diseases such as glomerulonephritis, thrombotic angiopathies, allograft rejection, and vasculitis. T cells predominantly infiltrate the tubulointerstitium, whereas monocytes are present in the tubulointerstitial and glomerular compartment. Because chemokines play a pivotal role in leukocyte trafficking under inflammatory conditions, this study investigated whether a differential expression of chemokines contributes to the precise coordination of leukocyte subtype trafficking in a rat model of renal microvascular endothelial injury. Renal microvascular endothelial injury was induced in rats by selective renal artery perfusion with an anti-endothelial antibody. Induction of the disease led to severe glomerular and tubulointerstitial endothelial injury with subsequent upregulation of chemokines followed by inflammatory cell recruitment. Among the analyzed chemokine mRNA, IP-10/CXCL10 (119-fold), acting via CXCR3 on activated T cells, and MCP-1/CCL2 (65-fold), acting via CCR2 on monocytes, were by far the most strongly upregulated chemokines. In situ hybridization revealed that IP-10/CXCL10 mRNA was selectively expressed by endothelial cells in the tubulointerstitial area, co-localizing with infiltrating T cells. Despite extensive damage of glomerular vasculature, no IP-10/CXCL10 expression by glomerular endothelial cells was detected. MCP-1/CCL2 mRNA in contrast was detectable in the glomerulus and the tubulointerstitium. Treatment with a neutralizing anti-IP-10/CXCL10 antibody significantly reduced the number of infiltrating tubulointerstitial T cells without affecting monocyte migration and led to an improved renal function. Our study demonstrates a role of IP-10/CXCL10 on T cell recruitment in a rat model of renal endothelial microvascular injury. Furthermore, a differential chemokine expression profile by endothelial cells in different renal compartments was found. These findings are consistent with the hypothesis that functional heterogeneity of endothelial cells from different vascular sites exists and provide an insight into the molecular mechanisms that may mediate compartment-specific T cell and monocyte recruitment in inflammatory renal disease.
authors.affiliation: Medizinische Klinik IV, Zentrum für Innere Medizin, University of Hamburg, Martinistrasse 52, Hamburg 20246, Germany. panzer@uke.uni-hamburg.de
authors.forename: Ulf
authors.initials: U
authors.lastname: Panzer
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Steinmetz
authors.forename: Rüdiger R
authors.initials: RR
authors.lastname: Reinking
authors.forename: Tobias N
authors.initials: TN
authors.lastname: Meyer
authors.forename: Susanne
authors.initials: S
authors.lastname: Fehr
authors.forename: André
authors.initials: A
authors.lastname: Schneider
authors.forename: Gunther
authors.initials: G
authors.lastname: Zahner
authors.forename: Gunter
authors.initials: G
authors.lastname: Wolf
authors.forename: Udo
authors.initials: U
authors.lastname: Helmchen
authors.forename: Patrick
authors.initials: P
authors.lastname: Schaerli
authors.forename: Rolf A K
authors.initials: RA
authors.lastname: Stahl
authors.forename: Friedrich
authors.initials: F
authors.lastname: Thaiss
mesh_terms: D000818:Animals; D054357:Chemokine CXCL10; D018925:Chemokines / Q000378:metabolism; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005921:Glomerulonephritis / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019707:Receptors, Chemokine / Q000378:metabolism
chemical_list: D054357:Chemokine CXCL10; D018925:Chemokines; D019743:Chemokines, CXC; C091326:Cxcl10 protein, rat; D012333:RNA, Messenger; D019707:Receptors, Chemokine