Altered renal tubular expression of the complement inhibitor Crry permits complement activation after ischemia/reperfusion.
Ischemia/reperfusion (I/R) of several organs results in complement activation, but the kidney is unique in that activation after I/R occurs only via the alternative pathway. We hypothesized that selective activation of this pathway after renal I/R could occur either because of a loss of complement inhibition or from increased local synthesis of complement factors. We examined the relationship between renal complement activation after I/R and the levels and localization of intrinsic membrane complement inhibitors. We found that loss of polarity of complement receptor 1-related protein y (Crry) in the tubular epithelium preceded activation of the alternative pathway along the basolateral aspect of the tubular cells. Heterozygous gene-targeted mice that expressed lower amounts of Crry were more sensitive to ischemic injury. Furthermore, inhibition of Crry expressed by proximal tubular epithelial cells in vitro resulted in alternative pathway-mediated injury to the cells. Thus, altered expression of a complement inhibitor within the tubular epithelium appears to be a critical factor permitting activation of the alternative pathway of complement after I/R. Increased C3 mRNA and decreased factor H mRNA were also detected in the outer medulla after I/R, suggesting that altered synthesis of these factors might further contribute to complement activation in this location.
Thurman
Joshua M
JM
Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. Joshua.Thurman@UCHSC.edu
Ljubanović
Danica
D
Royer
Pamela A
PA
Kraus
Damian M
DM
Molina
Hector
H
Barry
Nicholas P
NP
Proctor
Gregory
G
Levi
Moshe
M
Holers
V Michael
VM
D000818:Animals; D000954:Antigens, Surface; D003167:Complement Activation / Q000502:physiology*; D003165:Complement System Proteins / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface; D011951:Receptors, Complement / Q000235:genetics / Q000378:metabolism*; D017463:Receptors, Complement 3b; D015427:Reperfusion Injury / Q000276:immunology* / Q000473:pathology
D000954:Antigens, Surface; C081470:Cr1l protein, mouse; C513105:Cr1l protein, rat; D011956:Receptors, Cell Surface; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D003165:Complement System Proteins