Abstract
In a recent study, we identified a fucosylated damage‐associated ligand exposed by ischemia on renal tubule epithelial cells, which after recognition by collectin‐11 (CL‐11 or collectin kidney 1 (CL‐K1)), initiates complement activation and acute kidney injury. We exploited the ability to increase the local tissue concentration of free l‐fucose following systemic administration, in order to block ligand binding by local CL‐11 and prevent complement activation. We achieved a thirty‐five‐fold increase in the intrarenal concentration of l‐fucose following an IP bolus given before the ischemia induction procedure ‐ a concentration found to significantly block in vitro binding of CL‐11 on hypoxia‐stressed renal tubule cells. At this l‐fucose dose, complement activation and acute post‐ischemic kidney injury are prevented, with additional protection achieved by a second bolus after the induction procedure. CL‐11−/− mice gained no additional protection from l‐fucose administration, indicating that the mechanism of l‐fucose therapy was largely CL‐11‐dependent. The hypothesis is that a high dose of l‐fucose delivered to the kidney obstructs the carbohydrate recognition site on CL‐11 thereby reducing complement‐mediated damage following ischemic insult. Further work will examine the utility in preventing post‐ischemic injury during renal transplantation, where acute kidney injury is known to correlate with poor graft survival.
Highlights
A barrier to successful renal transplantation is the presence of ischemia/reperfusion (I/R) injury, affecting a third of transplants.[1]
C3-deficient mice are protected from I/R injury, demonstrating the central role of C3.22 Further research in the same model has both ruled out classical pathway involvement and demonstrated a key role for mannose binding lectin-associated serine protease (MASP)-2,5 it should be noted that MASP-2 can bypass C4 when complexed with mannose binding lectin (MBL).[23]
Our study provides a rational basis for considering l-fucose a potential therapeutic approach to the inhibition of renal I/R injury
Summary
A barrier to successful renal transplantation is the presence of ischemia/reperfusion (I/R) injury, affecting a third of transplants (rising to a half when the donated organ is taken following circulatory arrest).[1]. C3-deficient mice are protected from I/R injury, demonstrating the central role of C3.22 Further research in the same model has both ruled out classical pathway involvement and demonstrated a key role for MASP-2,5 it should be noted that MASP-2 can bypass C4 when complexed with MBL.[23] Most recently, CL-11 binding has been shown to increase following ischemic injury and is associated with the deposition of complement This effect is initiated through interaction of CL-11 with l-fucose, suggesting that the CRD on CL-11 recognizes a fucosylated ligand on ischemic tissue.[13] l-fucose is a deoxyhexose and a component of a number of glycans that have roles in various biological processes such as. This study uses a well-established mouse I/R injury to investigate this hypothesis.[5,13,22]
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