Connexin40 Is Essential for the Pressure Control of Renin Synthesis and Secretion

Abstract

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.)

Connexin 40 Mediates the Tubuloglomerular Feedback Contribution to Renal Blood Flow Autoregulation

“…1,2 Genetic ablation of Cx40 causes severe impairment of conducted vasodilator responses in arterioles, 3,4 uncoordinated vasomotion, 5 and hypertension. [5][6][7] Furthermore, vascular expression of Cx40 is reduced in genetically hypertensive rats. 8 Within the kidney, gap junctions are prevalent in the juxtaglomerular apparatus (JGA).…”

Minding the Gap

“…15 Interestingly, both Cx40A96S mice and mice with renin cell-specific deletion of Cx40 maintain the ability to recruit additional renin-producing cells in response to salt depletion and treatment with an angiotensin converting enzyme (ACE) inhibitor, while those with global deletion of Cx40 do not. 3,5,6 These observations suggest that gap junctional coupling is not required for recruitment of additional renin cells during homeostatic challenges, but it appears to be necessary for proper localization of these cells both under basal conditions and during prolonged renin stimulation. It is also possible that a structural or scaffolding function of Cx40 hemi-channels in nonrenin cells 16 may be required for this process.…”

“…Although the nature of the renal baroreceptor has been deliberated for nearly 40 years, 2 the molecular mechanisms underlying pressure control of renin release have remained elusive. Previous work by Kurtz and colleagues [3][4][5] and others 6 has established a key role for connexin proteins in this process. Much has been learned from transgenic mouse models with alterations in connexins, including globally-deficient connexin40 (Cx40) knockout mice, 5,6,7 renin cell-specific Cx40 knockout mice, 3 and now from mice expressing a novel point mutation in Cx40, as reported in this issue of JASN.…”

“…8 Disruption of Cx40 leads to loss of pressure control of renin secretion and development of hypertension. 6,5,3 In this issue of JASN, Lubkemeier et al 8 report their findings in a new transgenic mouse model that expresses a missense mutation in exon 2 of the connexin40 gene (Cx40A96S). This same loss-of-function mutation was previously identified in a human patient with idiopathic atrial fibrillation.…”

“…5 Therefore, assessment of the physiologic effects of the Cx40A96S mutation in mice furthers our understanding of renin regulation and BP control in humans.…”