Connexin40 regulates renin production and blood pressure

Abstract

Renin secretion is regulated by coordinated signaling between the various cells of the juxtaglomerular apparatus. The renin-secreting cells (RSC), which play a major role in the control of blood pressure, are coupled to each other and to endothelial cells by Connexin40 (Cx40)-containing channels. In this study, we show that Cx40 knockout (Cx40-/-) mice, but not their heterozygous littermates, are hypertensive due to the increase in the number of RSC, renin biosynthesis, and plasma renin. Treatment with the angiotensin II receptor AT1 antagonist candesartan or the angiotensin II-converting enzyme inhibitor ramipril reduced the blood pressure of the Cx40-/- mice to the same levels seen in wild-type (WT) mice. The elevated blood pressure of the knockout mice was not affected by clipping one renal artery (2K1C, renin-dependent model of hypertension) or after a high salt diet. Under these conditions, however, Cx40-/- mice showed an altered production and release of renin. The renin mRNA ratio between the clipped and the non-clipped kidney was lower in the knockout than in the WT 2K1C mice. This indicates that the response to a change in blood pressure was altered. The RSC of the Cx40-/- mice did not have a compensatory increase in the levels of either Cx43 or Cx37. Our data show that renin secretion is dependent on Cx40 and suggest the Cx40-/- mice may be a genetic model of renin-dependent hypertension.

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

“…Indeed, deletion of Cx40 leads to increased production of renin, ectopic renin expression, and loss of pressure-and angiotensin II (Ang II)-dependent control of renin release. 6,7,13 A rise in plasma renin concentration is also seen after administration of a putative Cx40-inhibiting peptide. 12 However, Cx40 expression is increased in response to a chronic reduction of renal perfusion pressure, a common stimulus for renin synthesis.…”

“…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.…”