Project #1: Chronic stimulation of renin cells and transformation of the kidney vasculature

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PROJECT SUMMARY/ABSTRACT Juxtaglomerular (JG) cells are sensors, perfected throughout evolution to interpret and respond to changes in blood pressure and the composition and volume of the extracellular fluid. Normally, renin release from JG cells suffice to maintain homeostasis. However, under intense and prolonged physiological challenges (dehydration, sodium depletion, hypotension) smooth muscle cells (SMCs) along the kidney arterioles reacquire the renin phenotype and restore homeostasis. Once homeostasis is reestablished, the transformed cells stop making renin and become SMCs again. Conversely, if the inciting threat is not removed or overcome [as in spontaneous or experimental mutations of the renin-angiotensin system (RAS) genes or chronic inhibition of the RAS in mice, rats and humans] the relentless chronic stimulation of renin cells leads to the concentric hypertrophy of intrarenal arteries and arterioles. Numerous hypertrophic renin cells surround -and insert chaotically within- the arteriolar walls. SMCs accumulate concentrically and inwardly, narrowing the vessel lumens and restricting blood flow, resulting in ischemia, fibrosis and renal failure. In spite of its medical importance, and the prevalent use of RAS inhibitors in children and adolescents, the mechanisms underlying the development of this severe, albeit silent, disease are not known. Our renin cell ablation studies indicated that renin cells are responsible for the vascular disease not only by physically participating in the thickening of the vessel wall but also by their direct cell-to-cell interaction with SMCs. Abundant preliminary data from our laboratory suggest that the cAMP and Notch pathways are responsible for the transformation of renin cells and the arterial disease. We hypothesize that under chronic unrestrained stimulation, p300 remodels the chromatin of renin cells leading them to a dual embryonic-senescent phenotype. Further, the transformed renin cells, via Notch activation induce the concentric vascular hypertrophy of the adjacent SMCs. Aim 1 will test the hypothesis that specific imprinted chromatin domains determine the progressive changes in cell fate responsible for the concentric arterial hypertrophy. Aim 1A will define the identity and fate of the cells that compose the diseased arterioles. Aim 1B will test whether cells derived from the diseased arterioles are retained in (or reverted to) an embryonic/progenitor state. Aim 2 will test the hypothesis that Histone acetyltransferase p300 is responsible for the generation of those chromatin domains that determine the pathological transformation of renin cells and the concentric arterial hypertrophy. Aim 3 will test the hypothesis that the concentric accumulation of adjacent SMCs is mediated by Notch signaling via the engagement of the Jagged1 ligand in renin cells with the Notch2 receptor in SMCs. Using novel conceptual and technical approaches, the proposed work will uncover the fundamental mechanisms, chromatin domains and transcriptional drivers responsible for the changes in cell fate leading to this severe arterial disease. The work has the potential to open new translational opportunities for the rational identification of targets for the design of specific therapies that protect the kidneys of children and adults with kidney diseases and hypertension.