Nitric oxide can directly mediate renin cell recruitment.

1 fit missing pieces into the puzzle of how renin production is controlled, when the demand for renin is high. Our understanding of the acute release of renin is much more complete than what we know about the long-term adaptations to stimuli of renin. Our scarce knowledge of the mechanisms mediating long-term renin stimulation is remarkable with regard to the clinical importance of renin. Hypertension, fluid and electrolyte homeostasis, as well as inflammation and fibrosis all may involve chronic renin stimulation. 2 More than 400 million years ago, renin first appeared in organisms, 3 and renin is often seen as the first hormone discovered. Shortly before the 20th century, Tigerstedt and Bergman showed that kidney extracts can elevate blood pressure, when intravenously infused. 4 Today, we recognize that the actions of renin go far beyond that of controlling blood pressure, and we have detailed insight into how renin is released into the circulation. 5 The major stimuli of short-term renin release are blood pressure decreases, β 1-adrenergic stimulation, and low salt, whereas the latter may require prostaglandin formation. 6 When stimuli for renin release persist over a longer period, 2 major distinct adaptations take place. The first is an induction of renin expression in the juxtaglomerular region. The second mechanism is metaplastic transformation of smooth muscle cells of preglomerular vessels. Metanephric mesenchymal cells are the origin of vascular smooth muscle cells and of renin precursor cells. 7 Interestingly, these renin precursor cells give rise to jux-taglomerular cells (JGCs) during ontogeny, and also to a subset of arteriolar smooth muscle cells. Of particular importance in the context of the study by Neubauer et al is that smooth muscle cells originating from the renin precursors are capable of undergoing metaplasia to renin-producing cells. 7 Increased renin gene expression along with hypertrophy of JGCs is found during long-term, enhanced renin release. In addition to the hypertrophy of juxtaglomerular cells, the abovementioned metaplastic transformation of preglomerular vascular smooth muscle cells into renin-producing cells can take place (Figure). How this is controlled remains largely unclear. It is here where Neubauer et al add to our understanding. Their work targets a novel role of endothelium-derived nitric oxide (NO), via its second messenger cGMP, on, what they term, renin recruitment in the afferent arteriole. In various different mouse models, low-salt diet was combined with angiotensin-converting enzyme inhibition to dramatically stimulate renin release, as well as to stimulate …