The origin, lineage relationships and morphogenesis of the kidney vasculature are not well understood. We hypothesize that the embryonic renal stromal compartment has at least two distinct early progenitor cells that give rise to all other cells of the kidney arterioles and their perivascular compartment: 1) A precursor of hemogenic endothelium (Scl+, hemangioblast) capable of giving rise to erythroid and endothelial cells (ECs) of the renal arteriole and 2) A Foxd1+ cell from which all other vascular and perivascular/adventitial cells originate. Further, renal hemangioblasts may give rise to Flk1+ precursors that in turn may contribute not only hemogenic ECs but also vascular SMCs. The lineage relationship among all these cell types has not been clarified and the mechanisms underlying the differentiation and assembly of the kidney arterioles are unclear. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid metabolite crucial in many biological processes, including angiogenesis. S1P1 and S1P3 are highly expressed in precursors and definitive cells of the kidney arteriole and may play an important role in the differentiation and assembly of arteriolar cells. The proposed studies will test two interrelated hypotheses: 1) The renal arterial tree originates from hemogenic and non-hemogenic- stromal cell precursors 2) Locally generated S1P (by hemogenic endothelium) interacting with S1P1 and S1P3 receptors is crucial for the maturation and assembly of the renal arterioles There is currently very limited information regarding the crucial events that govern the morphogenesis of the renal arterial tree. The proposed work will fill this important gap in our knowledge by defining the precise cellular origin and mechanisms whereby those early and intermediate precursors lead to the successful formation of the renal arterial tree, without which there is no functioning kidney. As designed, the proposed experiments will solve an existing challenge and generate new and exciting information of relevance to the fields of regeneration and hemo-vascular development with the potential to benefit children and adults with kidney and vascular diseases.

Public Health Relevance

The increasing prevalence of chronic renal disease represents an enormous health burden. Renal diseases have serious primary or secondary vascular lesions. These studies will explore the mechanisms whereby progenitor cells contribute to the endowment of renal vascular cells and their differentiation to form the renal arterioles and will generate relevant information to the fields of regeneration and hemo-vascular development with the potential to benefit children and adults with kidney and vascular diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
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Hoshizaki, Deborah K
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University of Virginia
Schools of Medicine
United States
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Tokonami, Natsuko; Mordasini, David; Pradervand, Sylvain et al. (2014) Local renal circadian clocks control fluid-electrolyte homeostasis and BP. J Am Soc Nephrol 25:1430-9
Gomez, R Ariel; Belyea, Brian; Medrano, Silvia et al. (2014) Fate and plasticity of renin precursors in development and disease. Pediatr Nephrol 29:721-6
Belyea, Brian C; Xu, Fang; Pentz, Ellen S et al. (2014) Identification of renin progenitors in the mouse bone marrow that give rise to B-cell leukaemia. Nat Commun 5:3273
Lin, E E; Sequeira-Lopez, M L S; Gomez, R A (2014) RBP-J in FOXD1+ renal stromal progenitors is crucial for the proper development and assembly of the kidney vasculature and glomerular mesangial cells. Am J Physiol Renal Physiol 306:F249-58
Berg, Alison C; Chernavvsky-Sequeira, Catalina; Lindsey, Jennifer et al. (2013) Pericytes synthesize renin. World J Nephrol 2:11-6
Moniwa, Norihito; Varagic, Jasmina; Ahmad, Sarfaraz et al. (2013) Hemodynamic and hormonal changes to dual renin-angiotensin system inhibition in experimental hypertension. Hypertension 61:417-24
Kurt, Birguel; Paliege, Alexander; Willam, Carsten et al. (2013) Deletion of von Hippel-Lindau protein converts renin-producing cells into erythropoietin-producing cells. J Am Soc Nephrol 24:433-44
Neubauer, Bjorn; Machura, Katharina; Kettl, Ramona et al. (2013) Endothelium-derived nitric oxide supports renin cell recruitment through the nitric oxide-sensitive guanylate cyclase pathway. Hypertension 61:400-7
Medrano, Silvia; Monteagudo, Maria C; Sequeira-Lopez, Maria Luisa S et al. (2012) Two microRNAs, miR-330 and miR-125b-5p, mark the juxtaglomerular cell and balance its smooth muscle phenotype. Am J Physiol Renal Physiol 302:F29-37