Michael S. Goligorsky It is becoming increasingly recognized that endothelial dysfunction may accompany acute renal diseases, such as acute renal failure. Damaged endothelium has been incriminated in the past in development of a 'no-reflow' phenomenon at early stages of acute renal ischemia. Using minimally invasive intravital videomicroscopy of glomerular and peritubular capillary blood flow immediately after ischemic insult to the rat kidney, we documented 'no-reflow' phenomenon manifested by the cessation, deceleration or reversal of blood flow, all occurring sporadically in pre- and post-glomerular microvasculature. Morphologic analysis revealed the loss of endothelial integrity in the renal microvasculature. Transplantation of functionally competent mature endothelial cells into the circulation of post-ischemic rats resulted in a remarkable protection of the kidney against ischemic injury. This functional protection was associated with the engraftment of transplanted cells into renal microcirculation. A similar, albeit less profound, effect was achieved by transplantation of surrogate cells expressing a single endothelium-specific enzyme, endothelial nitric oxide synthase (eNOS). Based on these findings we hypothesize that (I) endothelial dysfunction develops early in the course of ischemic acute renal failure, manifests a) structurally in the loss of endothelial integrity and b) functionally in the defective endothelium-dependent vasorelaxation. Furthermore, the observed renoprotective effect of transplanted endothelial cells leads to the second hypothesis that (11)the preexisting circulating endothelial cells or endothelial progenitor cells could be 'boosted' to improve natural defenses against renal ischemia, thus supplanting the need to transplant exogenous and heterologous cells. Therefore, the current proposal seeks t) to establish a more detailed mechanistic view on the renoprotective effect of transplanted differentiated endothelial cells in renal ischemia; 2) to obtain information on the population of circulating endothelial cells and their progenitors in acute renal ischemia, 3) to investigate possible strategies for preconditioning leading to the increased mobilization and accelerated maturation of these cells derived from endogenous sources, and 4) to identify the optimal conditions for harvesting and in vitro expansion of endothelial progenitors as a possible exogenous source of autologous endothelial cells. To accomplish these goals, in vitro and in vivo studies of endothelial cell engrafting into damaged microvasculature, stimulation of recruitment of endogenous endothelial progenitor cells, and optimization of ex vivo expansion of endothelial progenitor cells will be performed to evaluate the efficacy of these maneuvers in preventing ischemic renal injury. It is anticipated that novel therapeutic strategies should be disclosed, which could be applicable to prevention of acute renal failure. New York Medical College Department of Medicine Division of Nephrology and Hypertension Valhalla, NY 10595 Principal Investigator: Michael S. Goligorsky Co-Investigators Professor Z. Darzynkiewicz, MD, PhD - Brander Cancer Research Institute, New York Medical College Asst. Professor E. Noiri, MD, PhD - Department of Medicine, The Tokyo University Assoc Professor T. Yamamoto, MD - Department of Surgery and Biomedical Engineering, Kawasaki Medical School Consultants: Professor P. Anversa - Cardiology Research Institute, NYMC Professor I. Schwartz - Dept of Biochemistry, NYMC Professor J. Etlinger- Dept of Cell Biology, NYMC ========================================Section End===========================================
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