Pathophysiological Contributions of Fucosyltransferases in Renal Ischemia Reperfusion Injury

Abstract

Ischemia reperfusion injury (IRI) is a major cause of delayed graft function. Recent studies have shown that selectins play an important role in IRI. Selectins bind to sialylated and fucosylated sLex receptors, and two enzymes, fucosyltransferase IV (FucT-IV) and VII (FucT-VII), are important in the function of these receptors. We hypothesized that fucosyltransferase (FucT) enzymes were important pathophysiologic mediators of renal IRI. We therefore evaluated renal IRI in mice deficient in FucT-IV, FucT-VII, and both FucT-IV and FucT-VII and compared their renal function, tubular injury, selectin ligand expression, and neutrophil infiltration to those in wild-type control mice. Bilateral 30-min renal IRI was performed, and the results demonstrated that mice deficient in both FucT-IV/FucT-VII were significantly protected from renal IRI at 24 and 48 h compared with wild-type control mice. FucT-IV-deficient mice showed only modest protection from renal injury at 24 h. However, FucT-VII-deficient mice had similar injury as wild-type mice. Histological analysis of kidney tissue postischemia revealed that mice deficient in both FucT-IV and FucT-VII had significantly reduced tubular injury compared with wild-type mice. Selectin ligand expression increased postischemia in wild-type, but not FucT-IV/FucT-VII-deficient, mice. Neutrophil infiltration in postischemic kidneys of FucT-IV/FucT-VII-deficient mice was also attenuated. These data demonstrate that fucosyltransferases are important in the pathogenesis of renal IRI and are potential therapeutic targets.

Expression and regulation of fucosyltransferase 4 in human endometrium

“…Leukocyte rolling is mediated by a class of adhesion molecules known as selectins (Lasky 1992), which bind to sialylated and fucosylated oligosaccharide antigens such as Le x and sLe x . Regulated specific expression of the a1,3 fucosyltransferases responsible for fucosylation controls the expression of these antigens (Burne & Rabb 2002). Leukocyte homing was eliminated in mice that lack both FUT4 and FUT7 (Homeister et al 2001).…”

“…In addition, data from Weninger et al (2000) showed that FUT4 is crucial for the selectinmediated slow rolling of leukocytes on endothelial cells. FUT4 was the first leukocyte-associated enzyme linked to selectin ligand synthesis (Goelz et al 1990, 1994, Burne & Rabb 2002, such as Le The similarities between leukocyte rolling on endothelial cells and the initial stages of blastocyst attachment to the endometrial epithelium in humans have been recognized in recent years (Genbacev et al 2003, Dominguez et al 2005. The L-selectin system has also been shown to be important in the initial contact of the trophoblast to the luminal epithelium of human endometrium.…”

Therapeutic translation in acute kidney injury: the epithelial/endothelial axis

“…Blockade of the shared ligand to all three selectins (E-, P-, and L-selectin), which appears to be dependent on the presence of a key fucosyl sugar on the selectin ligand, led to reduced injury and mortality. Further, mice genetically deficient for E-selectin or P-selectin or both were completely protected in the cecal ligation and puncture model (CLP), a preclinical model for sepsis (88,89).…”

Identification of Neutrophil Gelatinase-Associated Lipocalin as a Novel Early Urinary Biomarker for Ischemic Renal Injury

“…We used murine models in which the structural and functional consequences of brief periods of renal ischemia have been documented (11)(12)(13)(14)(15). The characteristic histopathologic features of ischemic injury were readily evident in the 24-h reperfusion samples after both unilateral (45 min) and bilateral (30 min) ischemia.…”

“…We used well-established murine models in which the structural and functional consequences of brief periods of renal ischemia have been previously documented (11)(12)(13)(14)(15). Briefly, male Swiss-Webster mice (Taconic Farms, Germantown, NY) weighing 25 to 35 g were housed with 12:12-h light:dark cycle and were allowed free access to food and water.…”