Reduction of severe ischemia/reperfusion injury in rat kidney grafts by a soluble P-selectin glycoprotein ligand.

Abstract

Inflammatory leukocyte-endothelium interactions, mediated by selectins, contribute to renal ischemia/reperfusion (I/R) injury. We examined the influence of the soluble P-selectin glycoprotein ligand 1 (sPSGL) on early I/R-induced changes in a rat kidney transplantation model with long cold ischemia. After 24 hr of cold storage, syngeneic kidneys were grafted into bilaterally nephrectomized rats. Before transplantation, recipients received either 1 mg/kg of sPSGL or vehicle (n=8 per group). Six hours after reperfusion, grafts were removed for light microscopy and immunohistochemistry. Capillary blood flow was measured under a fluorescence microscope by using the concentric-circles method. A greater proportion, 74.7+/-7.2% (sPSGL) vs. 28+/-7.4% (controls), of all dye-labeled outer medullary capillaries appeared in the 12-microm radius (P<0.01), indicating dense blood flow, whereas 7.6+/-2.9% vs. 43.3+/-9.7%, respectively, appeared in the 60-microm radius (P<0.05), indicating rarefied blood flow. In the sPSGL-treated group, the extent of severe tubular damage within the inner stripe of the outer medulla was lower compared with controls (37.5+/-8.3% vs. 78.4+/-3.5%, P<0.01). Outer medullary heat shock protein 72 expression was 14.5+/-1.6% in the sPSGL-treated group compared with 9.6+/-1.4% in controls (P<0.05). The number of infiltrating polymorphonuclear leukocytes was similar in both groups. Treatment with sPSGL had no influence on the serum creatinine level. Our data suggest that impairment of outer medullary blood flow is crucial in I/R injury of kidney grafts with prolonged cold storage. Reduction of capillary blood flow perturbations by sPSGL protects tubular cells from severe structural damage. Blocking early selectin-mediated leukocyte adhesion may have therapeutic implications in improving the prognosis of renal transplants with severe I/R injury.