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

J Clin Invest. 2006 Feb;116(2):357-68. doi: 10.1172/JCI24521. Epub 2006 Jan 26.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, Surface
  • Complement Activation / physiology*
  • Complement System Proteins / metabolism*
  • Epithelial Cells / metabolism
  • Epithelial Cells / ultrastructure
  • Humans
  • Kidney Tubules, Proximal / cytology
  • Kidney Tubules, Proximal / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Cell Surface
  • Receptors, Complement / genetics
  • Receptors, Complement / metabolism*
  • Receptors, Complement 3b
  • Reperfusion Injury / immunology*
  • Reperfusion Injury / pathology


  • Antigens, Surface
  • Cr1l protein, mouse
  • Cr1l protein, rat
  • Receptors, Cell Surface
  • Receptors, Complement
  • Receptors, Complement 3b
  • Complement System Proteins