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===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052783-07
Application #
6836030
Study Section
General Medicine B Study Section (GMB)
Program Officer
Wilder, Elizabeth L
Project Start
1997-08-01
Project End
2007-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
7
Fiscal Year
2005
Total Cost
$367,775
Indirect Cost
Name
New York Medical College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041907486
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Matsumoto, Kei; Xavier, Sandhya; Chen, Jun et al. (2017) Instructive Role of the Microenvironment in Preventing Renal Fibrosis. Stem Cells Transl Med 6:992-1005
Song, J W; Zullo, J A; Liveris, D et al. (2017) Therapeutic Restoration of Endothelial Glycocalyx in Sepsis. J Pharmacol Exp Ther 361:115-121
Lipphardt, Mark; Song, Jong W; Matsumoto, Kei et al. (2017) The third path of tubulointerstitial fibrosis: aberrant endothelial secretome. Kidney Int 92:558-568
Kida, Yujiro; Zullo, Joseph A; Goligorsky, Michael S (2016) Endothelial sirtuin 1 inactivation enhances capillary rarefaction and fibrosis following kidney injury through Notch activation. Biochem Biophys Res Commun 478:1074-9
Zullo, Joseph A; Fan, Jie; Azar, Tala T et al. (2016) Exocytosis of Endothelial Lysosome-Related Organelles Hair-Triggers a Patchy Loss of Glycocalyx at the Onset of Sepsis. Am J Pathol 186:248-58
Lin, Chi Hua Sarah; Chen, Jun; Zhang, Zhongtao et al. (2016) Endostatin and transglutaminase 2 are involved inĀ fibrosis of the aging kidney. Kidney Int 89:1281-92
Kida, Yujiro; Goligorsky, Michael S (2016) Sirtuins, Cell Senescence, and Vascular Aging. Can J Cardiol 32:634-41
Goligorsky, M S; Hirschi, K (2016) Stress-Induced Premature Senescence of Endothelial and Endothelial Progenitor Cells. Adv Pharmacol 77:281-306
Zullo, Joseph A; Nadel, Ellen P; Rabadi, May M et al. (2015) The Secretome of Hydrogel-Coembedded Endothelial Progenitor Cells and Mesenchymal Stem Cells Instructs Macrophage Polarization in Endotoxemia. Stem Cells Transl Med 4:852-61
Zullo, Joseph; Matsumoto, Kei; Xavier, Sandhya et al. (2015) The cell secretome, a mediator of cell-to-cell communication. Prostaglandins Other Lipid Mediat 120:17-20

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