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

Abstract

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.

• Authors: Joshua M Thurman, Danica Ljubanović, Pamela A Royer, Damian M Kraus, Hector Molina, Nicholas P Barry, Gregory Proctor, Moshe Levi, V Michael Holers
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 116 Issue 2 Pg. 357-68 (Feb 2006) ISSN: 0021-9738 [Print] United States
• PMID: 16444293 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

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