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
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Gomez, R Ariel; Sequeira-Lopez, Maria Luisa S (2018) Renin cells in homeostasis, regeneration and immune defence mechanisms. Nat Rev Nephrol 14:231-245
Mohamed, Tahagod; Sequeira-Lopez, Maria Luisa S (2018) Development of the renal vasculature. Semin Cell Dev Biol :
Gomez, R Ariel; Lopez, Maria Luisa S Sequeira (2017) Plasticity of Renin Cells in the Kidney Vasculature. Curr Hypertens Rep 19:14
Oka, Masafumi; Medrano, Silvia; Sequeira-L?pez, Maria Luisa S et al. (2017) Chronic Stimulation of Renin Cells Leads to Vascular Pathology. Hypertension 70:119-128
Hu, Yan; Belyea, Brian C; Li, Minghong et al. (2017) Identification of cardiac hemo-vascular precursors and their requirement of sphingosine-1-phosphate receptor 1 for heart development. Sci Rep 7:45205
Song, Renfang; Lopez, Maria Luisa S Sequeira; Yosypiv, Ihor V (2017) Foxd1 is an upstream regulator of the renin-angiotensin system during metanephric kidney development. Pediatr Res 82:855-862
Hickmann, Linda; Steglich, Anne; Gerlach, Michael et al. (2017) Persistent and inducible neogenesis repopulates progenitor renin lineage cells in the kidney. Kidney Int 92:1419-1432
Gomez, R Ariel (2017) Fate of Renin Cells During Development and Disease. Hypertension 69:387-395
Shinohara, Keisuke; Liu, Xuebo; Morgan, Donald A et al. (2016) Selective Deletion of the Brain-Specific Isoform of Renin Causes Neurogenic Hypertension. Hypertension 68:1385-1392
Sequeira-Lopez, Maria Luisa S; Torban, Elena (2016) New insights into precursors of renal endothelium. Kidney Int 90:244-246

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