Deciphering the Identity of Renin Cells in Health and Disease.

Hypotension and changes in fluid-electrolyte balance pose immediate threats to survival. Juxtaglomerular cells respond to such threats by increasing the synthesis and secretion of renin. In addition, smooth muscle cells (SMCs) along the renal arterioles transform into renin cells until homeostasis has been regained. However, chronic unrelenting stimulation of renin cells leads to severe kidney damage. Here, we discuss the origin, distribution, function, and plasticity of renin cells within the kidney and immune compartments and the consequences of distorting the renin program. Understanding how chronic stimulation of these cells in the context of hypertension may lead to vascular pathology will serve as a foundation for targeted molecular therapies.

Super-enhancers maintain renin-expressing cell identity and memory to preserve multi-system homeostasis.

Renin cells are crucial for survival - they control fluid-electrolyte and blood pressure homeostasis, vascular development, regeneration, and oxygen delivery to tissues. During embryonic development, renin cells are progenitors for multiple cell types that retain the memory of the renin phenotype. When there is a threat to survival, those descendants are transformed and reenact the renin phenotype to restore homeostasis. We tested the hypothesis that the molecular memory of the renin phenotype resides in unique regions and states of these cells' chromatin. Using renin cells at various stages of stimulation, we identified regions in the genome where the chromatin is open for transcription, mapped histone modifications characteristic of active enhancers such as H3K27ac, and tracked deposition of transcriptional activators such as Med1, whose deletion results in ablation of renin expression and low blood pressure. Using the rank ordering of super-enhancers, epigenetic rewriting, and enhancer deletion analysis, we found that renin cells harbor a unique set of super-enhancers that determine their identity. The most prominent renin super-enhancer may act as a chromatin sensor of signals that convey the physiologic status of the organism, and is responsible for the transformation of renin cell descendants to the renin phenotype, a fundamental process to ensure homeostasis.