Renin cell fate in the kidney vasculature

University Of Virginia, Charlottesville VA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): The mechanisms controlling the identity of renin cells are unknown. During embryonic development renin precursor cells are present in the undifferentiated metanephric mesenchyme. Later in fetal and new born life renin cells are also found in large intrarenal arteries. As maturation continues, the number of renin cells diminishes as they become restricted to the classical juxtaglomerular localization found in the adult mammal. If an adult animal is subjected to manipulations that threaten blood pressure and fluid-electrolyte homeostasis, there is an increase in the number of renin-expressing cells (due to dedifferentiation of pre- existing adult cells) along the preglomerular arteries, inside the glomerulus, and in the kidney interstitium resembling the embryonic pattern. These studies suggested that the cells that have the plasticity to develop phenotypic characteristics of renin-expressing cells are those that expressed renin earlier in development. Using a mouse expressing ere recombinase under control of the renin locus (Ren1d-Cre) bred to a reporter, we showed that in the kidney, renin cells give rise to arteriolar smooth muscle, glomerular and interstitial cells and it is these cells that re-express renin in the adult when homeostasis is threatened. Thus, cells of the renin lineage conserve the plasticity to switch phenotypes according to the physiological need. The mechanisms that govern identity and plasticity of the renin cell have not been identified. Modifications of the histones in chromatin are associated with accessibility of the DNA to binding of transcription factors that control expression of genes. We hypothesize that identity and plasticity of the renin cell is determined by chromatin remodeling resulting from the balance between histone methylation and acetylation marks at the renin promoter. It is well known that cAMP regulates renin synthesis and release. Most of the transcriptional effects of cAMP are mediated by the binding of CREB /CBP/p300 to the cAMP response element (CRE) present in the enhancer region of the renin gene. Crebl and its coactivators have also been shown to regulate cell fate in other systems. Using our recently developed cell model we have shown that arteriolar smooth muscle cells of the renin lineage reacquire the renin cell phenotype upon stimulation by cAMP. Altogether these data suggest that Creb and its associated histone acetylases regulate renin cell specification. Using in vivo and in vitro approaches we will test the following hypotheses: 1. renin cells have a pattern of histone modifications (methylation, acetylation) at the renin gene that is characteristic of the state of differentiation of the cell and 2. Creb and its associated histone acetylases regulate identity and plasticity of the renin cell. Understanding the key molecules involved in renin cell specification and plasticity is relevant to blood pressure and fluid-electrolyte homeostasis. Findings from the proposed work may facilitate the development of new strategies for the prevention and treatment of hypertension and kidney diseases. [unreadable] [unreadable] [unreadable]