l‐Fucose prevention of renal ischaemia/reperfusion injury in Mice

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.

Complement in ischaemia–reperfusion injury and transplantation

“…The role of complement effectors in renal IRI has been extensively described [10,11]. In addition, more recent studies have identified a primary role for the lectin pathway of complement activation, in particular the contribution of the PRM known as collectin-11 (CL-11) and the potential for blocking its downstream effects [12,13]. Evidence points to a major fucosylated ligand recognized by CL-11 on hypoxic tissue [13] and has highlighted the feasibility to block CL-11 binding to this ligand by treatment with high concentrations of soluble L-fucose [12].…”

Fucose as a new therapeutic target in renal transplantation

“…The treatment was remarkable, since equilibration of free fucose within the renal space to a concentration 10 times the normal level partially protected the mice against loss of renal function induced by IRI. Mice lacking CL-11 gained no additional protection from L-fucose therapy, indicating that the therapeutic effect in this model was largely CL-11 dependent [48].…”

“…The biochemical nature of the fucosylated ligand on damaged tissue and the precise timing of its interaction with CL-11 need to be more fully understood to allow potential clinical exploitation. However, in theory, a large enough increase in local L-fucose concentration within the kidney will block CL-11 binding and/or activation of complement, and in doing so will protect the donor kidney from the effects of IRI, and this has been shown in mice [48]. L-fucose monosaccharide is an excellent candidate for this because a number of studies have shown its safety at high levels in both mice and humans.…”

“…Our lab is currently undertaking studies to optimise the treatment protocol, for example to achieve extended exposure of the kidney to high-dose fucose through repeated injection of donor mice allowing for rapid clearance from the serum and kidney. The technique could also be beneficial to other donor organs, such as the liver, since raised hepatic levels of Lfucose also follow systemic administration [48]. Finally, the work on CL-11 and localised inhibitory concentrations of blocking sugar underpins the importance of tissue synthesis of complement and pattern recognition molecules.…”

L‑fucose ameliorates the carcinogenic properties of Fusobacterium nucleatum in colorectal cancer

“…Currently, as our research team discovered that fucose is testified to competent in different types of diseases, including colitis, renal ischemia/reperfusion injury and high-fat diet-induced obesity and hepatic steatosis ( 10 , 24 , 25 ), it has also been demonstrated to impact the microbial ecosystem ( 11 ). Notably, fucose may decrease pathogen virulence through certain bacterium's metabolic pathway, such as Salmonella enterica ( 12 ).…”