Salt Intake and the Nitric Oxide-Cyclic AMP Signaling Pathway in Renin Secreting Cells

The protease renin is the key enzyme controlling the activity of the renin–angiotensin–aldosterone system. The release of renin from the kidneys into the circulation is controlled by ligands acting directly on renin-secreting cells such as adrenergic transmitters or hormones like angiotensin II. It is also essentially controlled by systemic factors such as the blood pressure or the sodium content of the body that require the generation of intermediate signals that are locally generated and that finally act directly on the renin-secreting cells.1 Renin-secreting cells are embedded in the juxtaglomerular cell complex containing also the macula densa cells of the distal tubule, the extraglomerular mesangium, and the preglomerular endothelium. It is in particular the endothelial cells and the macula densa cells that are prone to generate stimulatory intermediate signals such as prostaglandins and nitric oxide (NO). For this purpose, endothelial cells are equipped with COX-1 and NOS-3, whereas macula densa cells express COX-2 and NOS-1 in a regulated fashion.1 Sällström and co-workers have previously reported that the well-known and physiologically most relevant stimulation of renin secretion by low salt intake is absent in mice lacking NOS-1 in the macula densa, suggesting that macula densa–produced NO is a likely intermediate transmitter molecule linking salt deficiency to a stimulation of renin secretion.2 This assumption would fit with the observed coordinate regulation of NOS-1 and of renin expression.3 Meanwhile, NO is known to exert a broad spectrum of cellular effects ranging from buffering superoxide anions, nitrosylation of proteins to the activation of soluble guanylate cyclase starting the cyclic GMP (cGMP) signaling pathway. The cGMP pathway, in turn, may exert biological effects mainly via three subsequent pathways, namely by a direct effect of cGMP (for example, via activation of cyclic nucleotide–activated ion channels), activation of specific protein kinases (protein kinase G I and II), and via interference with the activity of cAMP degrading phosphodiesterases (PDEs). Cyclic GMP can enhance cAMP degradation by activation of PDE-2, but can also slow down cAMP degradation by binding to PDE-3. The existence of PDE-3, but not of PDE-2, has already been reported for renin-secreting cells.1 Their physiological involvement in NO-mediated action on renin-secreting cells in vivo has already been suggested.4 In their present paper, Sällström and co-workers5 now confirm the in vivo relevance of this pathway by providing evidence that the salt deficiency–induced NO action on renin secretion can be mimicked by inhibition of PDE-3 activity in vivo. Following now more established lines of signaling, inhibition of PDE-3 by NO/cGMP will elevate cAMP levels in renin-secreting cells, what is the best established and most powerful signal to stimulate renin secretion.1 Taking all findings of Sällström and co-workers together would suggest that low salt intake enhances NO production by the macula densa cells as a first step. NO then diffuses to adjacent renin-secreting cells and activates cGMP generation therein. Cyclic GMP in turn inhibits cAMP degradation via PDE-3 and finally stimulates renin secretion via the cAMP signaling route. The author declared no conflict of interest.