Regeneration of endothelial cells in the kidney by intrinsic cells

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The major aim of the application is the characterization and identification of relevant cells and signal pathways being responsible for the regeneration of microvascular endothelial injury in the kidney (glomerular and peritubular) in order to develop therapeutic strategies in future. Besides complement inhibition in atypical HUS, there are no specific therapeutic approaches at the moment aiming at protection and preservation of renal endothelial cells respectively or supporting their reparation. The basic research concept will be examined using our selective endothelial cell injury model of renal microangiopathy and supplemented by the renal ischemia reperfusion model.Due to previous very complex animal experiments, we know that no extrinsic cells are involved as substitute of local microvascular endothelial cells for the regeneration of the renal endothelium. On the other hand, local proliferating adult endothelial cells seem to have an essential but not exclusive part in the regeneration process. The experiments described in the application are able to characterize and quantify the dynamic of the renal endothelial cell pool. These experiments will be connected with the main question whether a non-endothelial (progenitor) cell pool exists in parallel to the local endothelial cell proliferation and is regulated if renal endothelial cell regeneration is needed. On one hand this grant application uses findings of the regeneration of other glomerular cells (of renin lineage cells) and on the other hand examines/characterizes mechanisms of cellular transdifferentiation and clonal expansion. By using several different transgenic mice especially with the inducible active, endothelial reporter system (Prof. Ralph Adams, Münster), the cellular regeneration of the endothelium will be analyzed closely longitudinal by FACS, immunohistochemistry and intravital microscopy. Especially the variety of different cellular tracing procedures with different reporter systems and different activity signs for adult endothelial cells, clonally derived (Brainbow), cell cycle-activated (Fucci mice) or endothelial cells emerging by neogenesis from non-endothelial cells (progenitor cells) will enable a general view of the involved endothelial regeneration mechanisms. By characterization of different adult endothelial cell and progenitor cell populations respectively (cell sorting) as well as clonally expanding endothelial cells during the regeneration process, significant cellular signatures will be decoded which are the basis for subsequent directed therapeutic modulation.