Compartment-specific expression and function of the chemokine IP-10/CXCL10 in a model of renal endothelial microvascular injury.
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.
Panzer
Ulf
U
Medizinische Klinik IV, Zentrum für Innere Medizin, University of Hamburg, Martinistrasse 52, Hamburg 20246, Germany. panzer@uke.uni-hamburg.de
Steinmetz
Oliver M
OM
Reinking
Rüdiger R
RR
Meyer
Tobias N
TN
Fehr
Susanne
S
Schneider
André
A
Zahner
Gunther
G
Wolf
Gunter
G
Helmchen
Udo
U
Schaerli
Patrick
P
Stahl
Rolf A K
RA
Thaiss
Friedrich
F
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
D054357:Chemokine CXCL10; D018925:Chemokines; D019743:Chemokines, CXC; C091326:Cxcl10 protein, rat; D012333:RNA, Messenger; D019707:Receptors, Chemokine