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Harnessing renal blood flow and oxygenation to manipulate differentiation of nephrons
Congenital kidney malformations are one of the leading causes of chronic kidney disease in children and young adults. The overall functional capacity of the kidney is dependent upon nephron progenitor differentiation to form the necessary number of nephrons. The appropriate formation of the developing kidney is inherently linked to the development of the renal vasculature. Formation of the renal vasculature involves two vascular processes angiogenesis, the sprouting of vessels from the major preexisting vessels (largely driven by blood flow) and vasculogenesis, the de novo formation of blood vessels via resident precursors (occurs in hypoxic environment). Few studies to date have examined the role of the renal vasculature and fetal blood flow (including oxygenation) in nephron formation and kidney development. Our laboratory has begun using innovative imaging techniques to investigate the development of vascular networks and fetal blood flow in embryonic mouse kidneys. Our preliminary data demonstrates that a complex vascular network (highly integrated with developing nephron structures), renal blood flow, and glomerular filtration occur early in kidney development. We propose to utilize three dimensional imaging techniques, combined with immunolabeling of developing vascular networks and nephron structures to interrogate how the interactions between these tissues influence the emergence of renal blood flow and filtration. In collaboration with Dr. Stolz, we will further define how the specialized vascular beds required for normal kidney function arise using immunogold electron microscopy. Finally, we will interrogate the role that blood flow and oxygenation play in mediating nephron progenitor differentiation.

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