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 1) to establish a more detailed mechanistic view on the renoprotective effect of transplanted differentiated endothelial cells in renalischemia; 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.
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 |
Papadimou, Evangelia; Morigi, Marina; Iatropoulos, Paraskevas et al. (2015) Direct reprogramming of human bone marrow stromal cells into functional renal cells using cell-free extracts. Stem Cell Reports 4:685-98 |
Schwarzenberger, Claudia; Sradnick, Jan; Lerea, Kenneth M et al. (2015) Platelets are relevant mediators of renal injury induced by primary endothelial lesions. Am J Physiol Renal Physiol 308:F1238-46 |
Showing the most recent 10 out of 96 publications