Project 2: Defining how the TGF- /FGF2 axis alters the fate of renin producing and vascular smooth muscle cells under conditions that threaten homoeostasis in infancy

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SUMMARY/ ABSTRACT Young children with salt wasting renal diseases are at high risk of developing chronic and severe extracellular fluid (ECF) volume contraction, leading to growth retardation and poor renal perfusion. Chronic conditions that threaten homeostasis such as hypotension, hypokalemia, salt depletion, and/or the prolonged used of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) in young children induce the recruitment of renin-producing cells with the resulting hypertrophy of the renal arterioles. This response however, cannot be sustained for too long without affecting renal perfusion. However, it is unclear what are the major vascular growth factors involved in this process, and how they affect the growth of renin producing cells. Previous studies, including our own preliminary work, suggest that Transforming Growth Factor-b (TGF-b) and Fibroblast Growth Factor-2 (FGF-2) interacting with Angiotensin II, play a key role modulating vascular tone, hypertrophy, and proliferation of juxtaglomerular (JG) and renal vascular smooth muscle cells (RVSMC). However, very little is known about the role that TGF-b and FGF-2 play in the regulation of renin release and the phenotype of renin producing cells in young infants. Here, we will test the hypothesis that under conditions that represent a physiological threat to maintain the ECF volume and/or renal perfusion in infancy, the Ang II-TGF-b and FGF-2 axis plays a critical role maintaining the normal fate and function of renin- producing cells and RVSMC. In addition, we hypothesize that when the balance between the RAS, TGF-b and FGF-2 pathways is disrupted, cells programed for the renin phenotype integrate in a disorderly manner inside the renal arterioles, precipitating the development of vascular concentric hypertrophic lesions leading to poor renal perfusion and kidney fibrosis. Using time and cell specific conditional deletion approaches, and single cell transcriptomic analysis, we will test this hypothesis in three aims. In aim 1 we will test hypothesis that a functional TGF-b receptor 1 signaling pathway in Ren1 + cells is necessary to sustain the hypertrophy of JG and RVSMC in response to chronic changes in dietary Na+ / K+ intake or RAS inhibition during early postnatal life, and determine how renin and the cAMP pathway interact with TGF-b and/or FGF-2 in JG and RVSMC to modulate their endocrine and contractile phenotypes. In aim 2, we will test the hypothesis that FGF signaling contributes to maintain the proper balance between the RAS and TGF-b in JG and RVSMCs under conditions of chronic RAS stimulation and suppression in young mice. In aim 3 we will define the transcriptome profile and protein changes that occur in renal arterioles and cells shed in the urine of young rats with poor renal perfusion induced by Na+ depletion and RAS inhibition, and validate these findings in cells and tissues derived from young infants undergoing similar conditions. These studies will elucidate new mechanisms whereby the RAS interacts with the TGF-b and FGF-2 pathways during infancy to modulate the growth of JG and RVSMCs, and maintain the ECF homeostasis and renal perfusion under conditions of chronic RAS stimulation or suppression in infancy.