Altered renal tubular expression of the complement inhibitor Crry permits complement activation after ischemia/reperfusion
Joshua M. Thurman, … , Moshe Levi, V. Michael Holers
Joshua M. Thurman, … , Moshe Levi, V. Michael Holers
Published February 1, 2006
Citation Information: J Clin Invest. 2006;116(2):357-368. https://doi.org/10.1172/JCI24521.
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Research Article Nephrology

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

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Figure 6

Complement deposition after I/R does not colocalize with Crry.

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Complement deposition after I/R does not colocalize with Crry. (A–C) Low...
(A–C) Lower-powered views (original magnification, ×100) of the kidney demonstrate that the deposition of C3 during reperfusion only occurred along tubules that lost basolateral expression of Crry. Glomeruli (arrowheads) indicate cortical tissue, and the outer medulla is shown toward the bottom of each frame. (A) At baseline, Crry was heavily expressed in the glomerulus and along the basolateral aspect of the tubules. (B) After 2 hours of reperfusion, the polarity of Crry in many tubules was disrupted. (C) After 24 hours of reperfusion, most of the tubules had diminished levels of Crry. C3 was extensively deposited along the proximal tubules. Some tubules retained normal Crry expression and polarization (arrows) and showed little C3 deposition. In areas of heavy C3 deposition, little colocalization of C3 and Crry (yellow) is seen. (D and E) Histograms of Crry and C3 staining at baseline (D) and after 24 hours of reperfusion (E) further demonstrate that little colocalization occurred. Pixels are mapped according to Crry and C3 intensity. (D) The heat map shows the relative population densities depicted by color. Pixels with a high intensity of both C3 and Crry are plotted in the upper right quadrant. (E) Even after 24 hours of reperfusion, when the population of pixels with a high C3 intensity was much increased, virtually none of these high C3 pixels demonstrated concurrent high-intensity staining for Crry.