HGF Signaling in Kidney Repair
Principal Investigator: Lloyd G Cantley
Abstract: Multiple events can lead to acute tubular injury and subsequent kidney dysfunction. Regardless of the mechanism of injury, successful kidney repair depends on three major factors, the survival of a sufficient number of tubular cells to effect the repair, the ability of those cells to de- differentiate, migrate and proliferate while maintaining the normal tubular architecture, and their ultimate re-differentiation to fully polarized epithelial phenotype. We believe that failure of prompt cell de-differentiation and survival leads to loss of tubular basement membrane integrity and subsequent tubule atrophy, whereas failure of re-differentiation triggers pro-fibrotic responses and progressive scarring. Hepatocyte growth factor is highly upregulated following acute tubular injury and has been shown in vitro to stimulate cell survival, activate phenotypic de-differentiation with epithelial spreading and migration, and yet to also support re- differentiation of epithelial cells to form complex tubes. Our preliminary in vitro data demonstrate that this switch from Hgf-induced cell de-differentiation to re-differentiation is regulated by the density (confluency) of the stimulated cells. We have now generated mice with conditional knock-out of the Hgf receptor in either the proximal tubule or collecting duct. Preliminary data from these mice confirms that Hgf regulates ureteric bud branching during development, and activates both pro-survival and anti-fibrotic pathways after tubule injury in the adult animal. The current proposal will utilize in vitro studies to define key signaling proteins that mediate Hgf- induced cell survival, cell differentiation, and organized wound repair, and then determine the function of those regulatory proteins in the actual process of reparative tubulogenesis using in vivo RNAi as well as our conditional knock-out mice. We believe that these studies of Hgf signaling in vitro and in vivo will give us important insights into the fundamental steps that regulate normal repair and provide a better understanding of how failure of those responses can lead to chronic kidney disease. It is our goal to use this knowledge for the rational design of interventions to promote the former while minimizing the latter. PUBLIC HEALTH RELEVANCE: The studies in this proposal are designed to help us understand the processes that regulate how the kidney repairs itself after injury. We will use cultured cells and mouse models of kidney injury to find out how the kidney cells are able to survive the injury, and how those that do survive are able to grow, divide and repair the tubules so that the kidney can function normally again. We believe that this information will help us to develop treatments to improve kidney repair in critically ill patients, and thus improve patient survival and decrease the need for dialysis.
Funding Period: 2003-07-01 - 2013-06-30
more information: NIH RePORT