RENIN CELL FATE IN THE KIDNEY VASCULATURE

University Of Virginia Charlottesville, Charlottesville VA

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Abstract

DESCRIPTION (Verbatim from the application): Renin cell progenitors originate in situ within the differentiating kidney rather than from extrarenal vessels. During early mouse embryonic development (E12), these cells are present in the undifferentiated metanephric mesenchyme, before vascularization of the kidney has occurred and before the hemodynamic functions of renin are needed. Later in fetal, life, renin cells are found along intrarenal arteries, in glomeruli, and among interstitial cells. With maturation, renin cells become restricted to the classical adult juxtaglomerular (JG) localization. If an adult animal is subjected to manipulations that threaten homeostasis, there is an increase in the number of renin-expressing cells along preglomerular arteries, interstitium and glomeruli resembling the embryonic pattern. It is likely that the ability of adult kidney cells to re-express renin depends on the lineage of the cell involved. It has been suggested that JO cells originate from smooth muscle cells. However, our preliminary data suggest just the opposite. The fate of renin cells remains to be studied. Similarly; the timing of appearance of these cells in branching points of differentiating renal arterioles suggests a role for JG cell precursors in the development of the kidney vasculature. Finally, some strains of mice have more than one renin gene: Ren 1 and Ren 2. The role of each of these genes in lineage determination and morphogenesis is unknown. Using in vivo fate mapping, chimeric mice, and cell ablation techniques we propose to adress the following hypotheses: (1) in addition to JG cells, renin cell precursors give rise to (rather than originate from) renal arteriolar smooth muscle cells, pericytes and mesangial cells, (2) renin cell descendants are the only kidney cells capable of metaplastic transformation to the renin phenotype, (3) expression of renin is necessary for JO cell and arteriolar differentiation and Ren I and Ren 2 regulate the differentiation of distinct and separate renin cells; (4) JG cells per se (independent of renin) are necessary for nephrovascular development. The studies should generate fundamental new knowledge on JG cell differentiation and function and open new avenues for the understanding, prevention and treatment of hypertension and kidney diseases.