The role and regulation of pericytes in remodeling the periarterial niche during nephrogenesis

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PROJECT SUMMARY/ABSTRACT Chronic kidney disease is a leading cause of death in the United States and places an immense burden on the healthcare system. Many cases of chronic kidney disease eventually result in renal fibrosis, which is characterized by deposition of excess extracellular matrix (ECM) by myofibroblasts and contributes to eventual organ failure. Recent studies have identified renal pericytes, a type of perivascular cell that surrounds endothelial cells of small vessels such as capillaries, as the source of myofibroblasts in fibrosis. Despite this characterized role in a major disease process, little is known about the developmental origin or role of pericytes. We have characterized a novel population of pericytes that surrounds arteries only during development, which we call periarterial pericytes. We have characterized the origin of these pericytes using murine genetic reporters. Furthermore, we have identified a potential regulator of pericyte migration, which is present in the kidney during development. This temporary guidance of periarterial pericytes implies an important role in arteriogenesis. Our preliminary data suggest that pericytes may be required for collagen production and vascular smooth muscle differentiation during nephrogenesis, mirroring their pathogenic role in fibrosis. Thus, the overall goal of this project is to define the role of periarterial pericytes during nephrogenesis in remodeling the ECM of the periarterial niche to support vascular smooth muscle maturation, as well as to elucidate the mechanism by their localization is regulated during development. We will utilize murine genetic lineage tracing tools, in addition to immunofluorescence staining and cutting edge in situ hybridization techniques, to trace the origin, fate, and gene expression of periarterial pericytes throughout development. We will selectively ablate pericytes in vivo to assess their requirement in arteriogenesis and smooth muscle coverage. Finally, we will utilize in vitro models to clarify intracellular interactions that are required for pericyte secretion of ECM and smooth muscle cell maturation, as well as to elucidate the mechanism by which pericyte migration is regulated. Collectively, these studies will characterize a novel role of pericytes during development, as well as elucidate molecular mechanisms that may be dysregulated in disease processes such as renal fibrosis. This information may inform future therapies for chronic kidney disease or regenerative medicine efforts, both which will be badly needed as the prevalence of kidney disease grows in the United States and abroad.