Are microRNAs the key to transforming renin progenitor cells in the afferent renal circulation?

RENIN, PRODUCED IN JUXTAGLOMERULAR (JG) cells at the glomerular terminus of the afferent arteriole, is the critical regulatory enzyme in the pathway of angiotensin formation. When the kidney is chronically stressed with the need to produce more renin (as in renal ischemia, sodium restriction, or with converting enzyme inhibition), a number of vascular smooth muscle cells upstream in the afferent arteriole and interlobular arteries are transformed into a renin-producing phenotype by a process referred to as “recruitment” (7–9). While early on it was thought that there was some transformation of regular afferent vascular smooth muscle cells to a renin-containing phenotype, the laboratories of Dr. Ariel Gomez at the University of Virginia, with a number of collaborators, have been at the forefront of studying the signaling and transformation of a distinct population of renin progenitor cells. These cells are not the typical vascular smooth muscle cells, as they have been genetically programmed to be involved in the embryonic progression of renin expression associated with the developing kidney that is lost to an adult vascular smooth muscle phenotype (5, 7–9). These progenitor cells have the ability to transform back into their fetal heritage of a renin-containing cell under certain conditions in which renal homeostasis is challenged. This was determined (7) using a clever technique of incorporating expression within the renin progenitor cells in a dual-labeling technique, revealing that when they are not expressing renin (in the vascular smooth muscle phenotype) they are marked with a cyan florescent protein and when they are expressing renin they are marked with a yellow fluorescent protein. Thus the metamorphosis from the adult smooth muscle phenotype back into the embryonic renin-producing phenotype distinctly identifies these cells from other smooth muscle cells in the afferent circulation following the recruitment stimulus. The pattern of the progenitor cell distribution throughout the renal vasculature at different stages of embryonic development has been described in elegant studies using three-dimensional reconstructions (5). We now more fully understand the characteristics of these cells and how they are involved in the recruitment process, but the signaling and the control of this metamorphosis have remained largely a mystery. cAMP is well established as the stimulatory second messenger which regulates renin secretion (1), and it has also been shown to be a critical factor in the stimulation and regulation of renin expression and synthesis via histone acetylation at the cAMP-response element (CRE) on the renin gene (7) under the control of the histone acetyl transferases CBP and p300 (2). These two transferases are essential for maintaining the integrity of the renin-containing phenotype. Interestingly, the production of cAMP linked to renin secretion is mediated selectively by the calcium-inhibitable isoform(s) of adenylyl cyclase (1, 3, 6), which colocalizes with the renin-containing granule (6), but it is not known whether the stimulation of cAMPmediated renin gene transcription and expression are also controlled through this calcium-mediated pathway or by another adenylyl cyclase isoform within the JG cell. Additionally, while cAMP mediates renin expression, it is not yet clear what its role in the signaling process of recruitment and metamorphosis of the progenitor cell into its renin-producing phenotype might be. So, the critical question is, what controls the “switch” in response to homeostatic challenge to transform these cells between their two phenotypes?