Small molecule selectin ligand inhibition improves outcome in ischemic acute renal failure

Nemoto, Takashi; Burne, Melissa J.; Daniels, Frank; O’Donnell, Michael P.; Crosson, John T.; Berens, Kurt L.; Issekutz, Andrew C.; Kasiske, Bertram L.; Keane, William F.; Rabb, Hamid

doi:10.1046/j.1523-1755.2001.00054.x

Cited by 94 publications

(46 citation statements)

References 32 publications

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“…Although ablation of the ICAM-1 gene and pretreatment with ICAM-1 antibody rendered mice resistant to ischemic AKI, human trials with anti-ICAM-1 mAb administered after ischemia did not prevent AKI in cadaveric transplant recipients (14). Similarly, gene knockouts, mAb, and pharmacologic inhibitor studies have suggested a role for E-and P-selectins (132)(133)(134). However, subsequent studies have shown that it is platelet P-selectin, not endothelial P-selectin, that is the key component leading to AKI (135).…”

Section: Alterations In the Microvasculaturementioning

confidence: 99%

Update on Mechanisms of Ischemic Acute Kidney Injury

Devarajan

2006

Journal of the American Society of Nephrology

901

759

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Section: Alterations In the Microvasculaturementioning

confidence: 99%

Update on Mechanisms of Ischemic Acute Kidney Injury

Devarajan

2006

Journal of the American Society of Nephrology

901

759

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“…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).…”

Section: Endotheliummentioning

confidence: 99%

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

Molitoris¹

2014

J. Clin. Invest.

177

204

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“…Although the inactive control was ineffective, a 50% inhibitory effect (IC 50 ) was achieved by BIMO at 500 M for E-selectin, 70 M for P-selectin, and 560 M for L-selectin. An in situ perfusion with BIMO before the I/R injury inflicted by bilateral artery clamping prevented mortality and improved kidney function (20). The damage caused by hemorrhagic shock was diminished after pretreatment with BIMO (21).…”

mentioning

confidence: 93%

Selectin Inhibitor Bimosiamose Prolongs Survival of Kidney Allografts by Reduction in Intragraft Production of Cytokines and Chemokines

Langer

Wang

Stepkowski

et al. 2004

Journal of the American Society of Nephrology

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Abstract. Binding of the P-, L-, and E-selectins to sialyl Lewis (CI Ͻ1 is synergistic; CI ϭ 1 is additive; and CI Ͼ1 is antagonistic). Similarly, BIMO interacted synergistically with sirolimus (CI ϭ 0.64) and FTY720 (CI ϭ 0.22). While the mechanism of immunosuppression was being analyzed, decreased infiltration of CD4 ϩ , CD8 ϩ , and macrophages on day 7 after grafting was observed. Multiple cytokines were also expressed, including IL-1␣, IL-1␤, IL-2, IL-4, IL-6, IL-10, IL-12, IL-18, TNF-␣, and IFN-␥ in kidney allografts on days 3, 5, and 7 after grafting, as measured by a ribonuclease protection assay. Furthermore, at similar time points, BIMO treatment reduced intragraft expression of P-selectin glycoprotein ligand-1, CX 3 CL1, CCL19, CCL20, and CCL2. Thus, BIMO blocks allograft rejection by reduction of intragraft expression of cytokines and chemokines.Whereas nearly all cells in an adult human are sessile, the majority of leukocytes provide a mobile defense of the individual's integrity (1). Precursors of leukocytes continuously undergo differentiation in the bone marrow and the thymus, whereas mature leukocytes continuously traffic between the spleen and the lymph nodes. Efficient deployment to an inflammatory site requires polarization, mobilization, and migration of leukocytes during processes that are controlled by adhesion molecules and chemokines (2). These molecules participate in the process of ischemia/reperfusion (I/R), as well as in acute and chronic rejection responses toward organ allografts (3,4).Adhesive interactions with the vascular endothelium initiate the migration of leukocytes to sites of inflammation. In this cascade of events (rolling, attachment, spreading, and transendothelial migration), the selectin family (P-, E-, and L-selectins) is largely involved in rolling and attachment (5). Rolling is initiated by the interaction of selectins with sialyl Lewis x (sLe x ) ligand (6); all selectins have an NH 2 -terminal, lectinlike domain binding to sLe x and other related ligands in a Ca 2ϩ -dependent manner (7). Two selectins are expressed on endothelial cells, namely, P-selectins, which are stored in granules and rapidly translocated to the cell surface, and E-selectins, which are induced by inflammatory cytokines (8). Within minutes after reperfusion, endothelial cells express P-selectins that mediate leukocyte rolling over the vascular lining.The main ligand for P-selectin is P-selectin glycoprotein ligand-1 (PSGL-1), which is a disulfide-bonded homodimeric mucin-like glycoprotein expressed on leukocytes, platelets, and CD34 ϩ cells (9). Functional PSGL-1 is modified with sialylation and fucosylation of O-linked sugars, as well as sulfation of tyrosine residues on the N-terminus (10). Engagement of PSGL-1 by P-selectins slows the movement of leukocytes and sparks a cascade of signaling pathways, leading to the expression of multiple adhesion molecules (11). During rolling, the leukocytes start expressing integrins triggered by cytokines and

show abstract

Small molecule selectin ligand inhibition improves outcome in ischemic acute renal failure

Abstract: Small molecule selectin ligand inhibition provides a novel and effective approach to attenuate ischemic acute renal failure. Timing of treatment is crucial to success.

Cited by 94 publications

References 32 publications

Update on Mechanisms of Ischemic Acute Kidney Injury

Update on Mechanisms of Ischemic Acute Kidney Injury

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

Selectin Inhibitor Bimosiamose Prolongs Survival of Kidney Allografts by Reduction in Intragraft Production of Cytokines and Chemokines

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