Epigenetic Mechanisms of Renin Cell Plasticity 412 views

Paramount to the survival of animals with a closed circulatory system is the regulation of blood pressure and blood flow to critical tissues. This is accomplished by the renin-angiotensin system (RAS), an enzymatic cascade that culminates in the production of Angiotensin II, a potent vasoconstrictor that controls blood pressure, renal hemodynamics and fluid-electrolyte homeostasis. Across millions of years of development, the RAS has been perfected throughout evolution to enable animals to survive fluctuations in fluid-electrolyte balance and blood pressure. The key event in the RAS and its rate limiting step is the tightly regulated synthesis and secretion of renin, a hormone-enzyme which cleaves angiotensinogen into Angiotensin I which is further converted to Angiotensin II by Angiotensin Converting Enzyme (ACE). Under normal physiologic conditions, renin is secreted by juxtaglomerular (JG) cells located in the walls of the afferent arterioles at the entrance to the glomeruli of the kidney. Although the nominal number of JG cells is small, representing 0.1-0.01% of all kidney cells4, their production of renin is, under normal conditions, typically sufficient to sustain blood pressure and ensure survival. However, during intense threats to homeostasis by hypotension, dehydration or administration of RAS inhibitors, mesangial cells, smooth muscle cells and pericytes along the afferent arterioles transform into renin expressing cells – a process described as “recruitment”. This process is a result of direct transdifferentiation of the aforementioned cell types in the kidney. These cells undergo a remarkable switch in cellular identity to express renin and other genes crucial to attain the renin cell program before presumably returning to their original identity once the threat abates and homeostasis is restored. The underlying mechanisms which bestow this rare and fascinating ability upon these cells remain unknown and are explored in this thesis.

PHD (Doctor of Philosophy)

Epigenetics; Cell Identity; Vascular Biology; Transdifferentiation

English

2022-08-02