The protease renin is the key enzyme of the renin-angiotensin-aldosterone cascade, which is relevant under both physiological and pathophysiological settings. The kidney is the only organ capable of releasing enzymatically active renin. Although the characteristic juxtaglomerular position is the best known site of renin generation, renin-producing cells in the kidney can vary in number and localization. (Pro)renin gene transcription in these cells is controlled by a number of transcription factors, among which CREB is the best characterized. Pro-renin is stored in vesicles, activated to renin, and then released upon demand. The release of renin is under the control of the cAMP (stimulatory) and Ca2+(inhibitory) signaling pathways. Meanwhile, a great number of intrarenally generated or systemically acting factors have been identified that control the renin secretion directly at the level of renin-producing cells, by activating either of the signaling pathways mentioned above. The broad spectrum of biological actions of (pro)renin is mediated by receptors for (pro)renin, angiotensin II and angiotensin-( 1 – 7 ).

Abstract-Renin secretion and synthesis in renal juxtaglomerular cells are controlled by short feed back loops involving angiotensin II and the intrarenal blood pressure. The operating mechanisms of these negative feed back regulators are widely unknown, except for the fact that both require calcium to exert their inhibitory action. We here show that in the absence of connexin40 (Cx40), which form gap junctions between juxtaglomerular and endothelial cells, the negative control of renin secretion and synthesis by angiotensin II and by intravasal pressure is abrogated, while the regulation by salt intake and ␤-adrenergic stimulation is maintained. Renin secretion from Cx40-deficient kidneys or wild-type kidneys treated with the nonselective gap junction blocker 18␣-glycyrrhetinic acid (10 mol/L) resembles the situation in wild-type kidneys in the absence of extracellular calcium. This disturbed regulation is reflected by an enhanced plasma renin concentration despite an elevated blood pressure in Cx40-deficient mice. These findings indicate that Cx40 connexins and likely intercellular communication via Cx40-dependent gap junctions mediate the calcium-dependent inhibitor effects of angiotensin II and of intrarenal pressure on renin secretion and synthesis. Because Cx40 gap junctions are also formed between renin producing cells and endothelial cells our finding could provide additional information to suggest that the endothelium may be strongly involved in the control of the renin system. (Circ Res. 2007;100:556-563.)

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In the adult kidney, renin-producing cells are typically located in the walls of afferent arterioles at the transition into the glomerular capillary network. The mechanisms that are responsible for restricting renin expression to the juxtaglomerular position are largely unknown. This study showed that in mice that lack connexin 40 (Cx40), the predominant connexin of renin-producing cells, renin-positive cells are absent in the vessel walls and instead are found in cells of the extraglomerular mesangium, glomerular tuft, and periglomerular interstitium. Blocking macula densa transport function by acute administration of loop diuretics strongly enhances renin secretion in vivo and in isolated perfused kidneys of wild-type mice. This effect of loop diuretics is markedly attenuated in vivo and even blunted in vitro in Cx40-deficient mice. Even after prolonged stimulation of renin secretion by severe sodium depletion, renin expression is not seen in juxtaglomerular cells or in cells of more proximal parts of the arterial vessel wall as occurs normally. Instead, renin remains restricted to the extra-/periglomerular interstitium in Cx40-deficient mice. In contrast to the striking displacement of renin-expressing cells in the adult kidney, renin expression in the vessels of the developing kidney was found to be normal. This is the first evidence to indicate that cell-to-cell communication via gap junctions is essential for the correct juxtaglomerular positioning and recruitment of renin-producing cells. Moreover, these findings support the notion that gap junctions are relevant for the macula densa signaling to renin-producing cells.

The aspartyl-protease renin is the key regulator of the renin-angiotensin-aldosterone system, which is critically involved in salt, volume, and blood pressure homeostasis of the body. Renin is mainly produced and released into circulation by the so-called juxtaglomerular epithelioid cells, located in the walls of renal afferent arterioles at the entrance of the glomerular capillary network. It has been known for a long time that renin synthesis and secretion are stimulated by the sympathetic nerves and the prostaglandins and are inhibited in negative feedback loops by angiotensin II, high blood pressure, salt, and volume overload. In contrast, the events controlling the function of renin-secreting cells at the organ and cellular level are markedly less clear and remain mysterious in certain aspects. The unravelling of these mysteries has led to new and interesting insights into the process of renin release.