Mannan-binding lectin mediates renal ischemia/reperfusion injury independent of complement activation.

Abstract

Ischemia/reperfusion injury (IRI) remains a major problem in renal transplantation. Clinical studies have identified that high serum levels of Mannan-binding lectin (MBL), the initiator of the lectin pathway of complement activation, are associated with inferior renal allograft survival. Using a rat model, we identified an entirely novel role for MBL in mediating renal IRI. Therapeutic inhibition of MBL was protective against kidney dysfunction, tubular damage, neutrophil and macrophage accumulation, and expression of proinflammatory cytokines and chemokines. Following reperfusion, exposure of tubular epithelial cells to circulation-derived MBL resulted in internalization of MBL followed by the rapid induction of tubular epithelial cell death. Interestingly, this MBL-mediated tubular injury was completely independent of complement activation since attenuation of complement activation was not protective against renal IRI. Our identification that MBL-mediated cell death precedes complement activation strongly suggests that exposure of epithelial cells to MBL immediately following reperfusion is the primary culprit of tubular injury. In addition, also human tubular epithelial cells in vitro were shown to be susceptible to the cytotoxic effect of human MBL. Taken together, these data reveal a crucial role for MBL in the early pathophysiology of renal IRI and identify MBL as a novel therapeutic target in kidney transplantation.

• Authors: P van der Pol, N Schlagwein, D J van Gijlswijk, S P Berger, A Roos, I M Bajema, H C de Boer, J W de Fijter, G L Stahl, M R Daha, C van Kooten
• Journal: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons (Am J Transplant) Vol. 12 Issue 4 Pg. 877-87 (Apr 2012) ISSN: 1600-6143 [Electronic] United States
• PMID: 22225993 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.

Chemical References

• Mannose-Binding Lectin

Topics

• Animals
• Cell Death
• Cells, Cultured
• Complement Activation (immunology)
• Flow Cytometry
• Humans
• Kidney Function Tests
• Kidney Tubules (drug effects, metabolism, pathology)
• Male
• Mannose-Binding Lectin (adverse effects)
• Rats
• Rats, Inbred Lew
• Renal Insufficiency (etiology, pathology)
• Reperfusion Injury (etiology, pathology)