Altered renal tubular expression of the complement inhibitor Crry permits complement activation after ischemia/reperfusion

Joshua M. Thurman, Danica Ljubanović, Pamela A. Royer, Damian M. Kraus, Hector Molina, Nicholas P. Barry, Gregory Proctor, Moshe Levi, V. Michael Holers

Research output: Contribution to journalArticlepeer-review

135 Scopus citations


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.

Original languageEnglish
Pages (from-to)357-368
Number of pages12
JournalJournal of Clinical Investigation
Issue number2
StatePublished - Feb 1 2006


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