Acute and chronic kidney diseases are common clinical problems with increasing incidence, serious consequences, and heavy financial strain. Despite decades of research and advances in patient-care, mortality rates for patients with acute kidney injury have not significantly decreased since the middle portion of the past century. The mammalian kidney has the inherent potential for regeneration and recovery of tubular function following acute injury, through recruitment and proliferation of surviving tubular epithelium. Limitation in the number of surviving tubular cells commonly leads to progressive loss of renal function with significant morbidity and mortality. Identification of renal cell precursors with significant tubulogenic potential could be therapeutically useful in severe or chronic forms of kidney disease. We have identified a novel intrarenal cell population, defined by co-expression of vascular-endothelial growth factor receptor-2 (Flk1) and stem cell antigen-1 (Sca1), in adult mouse kidney cortex. The Flk+/Sca1+ cells are capable incorporating into renal tubules after transplantation into injured kidneys. We hypothesize that the Flk+/Sca1+ cell population comprises a novel intrinsic renal progenitor cell population. This hypothesis will be tested with the following three aims: 1) Determine the phenotype and origin of Flk+/Sca1+ renal progenitor cells in normal adult mouse kidney, 2) Determine the ability of Flk+/Sca1+ cells to incorporate and repair kidney tubules after ischemic or toxic injury, and 3) Establish a role of Sca1 function in renal tubule homeostasis and repair. The experiments performed under each aim will test the hypothesis that Flk1 and Sca1 mark an intrinsic renal progenitor cell and will provide important new information about adult kidney repair and organ regeneration.
The work proposed here will provide novel insight into the mechanisms of adult kidney repair after injury, a common clinical problem. This new information will aid in the development of novel therapies for acute and chronic forms of kidney disease and will provide critical information to the fields of renal biology as well as organ regeneration.
|Camarata, Troy D; Weaver, Grant C; Vasilyev, Alexandr et al. (2015) Negative Regulation of TGF? Signaling by Stem Cell Antigen-1 Protects against Ischemic Acute Kidney Injury. PLoS One 10:e0129561|