The Connexin40 A96S Mutation Causes Renin-Dependent Hypertension

Abstract

Deletion of the gap-junction-forming protein connexin40 leads to renin-dependent hypertension in mice, but whether observed human variants in connexin40, such as A96S, promote hypertension is unknown. Here, we generated mice with the A96S variant in the mouse connexin40 gene. Although mice homozygous for the A96S mutations had normal expression patterns of connexin40 in the kidney, they were hypertensive, had sixfold higher plasma renin concentrations, and had 40% higher levels of renin mRNA than controls. Renin-expressing cells were aberrantly located outside the media layer of afferent arterioles, and increased renal perfusion pressure did not inhibit renin secretion from kidneys isolated from homozygous A96S mice. Treatment with a low-salt diet in combination with an ACE inhibitor increased renin mRNA levels, plasma renin concentrations, and the number of aberrantly localized renin-producing cells. Taken together, these findings suggest that the A96S mutation in connexin40 leads to renin-dependent hypertension in mice. Modulation of renin secretion by BP critically depends on functional connexin40; with the A96S mutation, the aberrant extravascular localization of reninsecreting cells in the kidney likely impairs the pressure-mediated inhibition of renin secretion.

Loss of Functional Endothelial Connexin40 Results in Exercise-Induced Hypertension in Mice

“…Global deletion of Cx40 (Cx40ko) or replacement of the endogenous Cx40 gene coding sequence with either Cx45 or a nonfunctional mutant Cx40A96S produces hypertension that is predominantly renal in origin. [7][8][9][10] Loss of functional Cx40 from the cardiac conduction system also results in arrhythmia.…”

“…10,20,21 When expressed in vitro, the Cx40A96S mutant forms electrically impaired gap junctions that act as a dominant-negative toward wtCx40. 18 We hypothesized that endothelial-specific expression of Cx40T152A would interfere with endogenous wtCx40, leading to impairment of ascending vasodilation and onset of exercise-induced hypertension, making the Cx40T152ATg mouse a suitable model in which to study the cardiovascular sequelae of this condition.…”

“…Global deletion of Cx40 (Cx40ko) or replacement of the endogenous Cx40 gene coding sequence with either Cx45 or a nonfunctional mutant Cx40A96S produces hypertension that is predominantly renal in origin. [7][8][9][10] Loss of functional Cx40 from the cardiac conduction system also results in arrhythmia.11,12 Interestingly, mice carrying an endothelial-specific deletion of Cx40 are reportedly normotensive 13 ; however, the effect of activity was not investigated. Our laboratory recently developed the Cx40T202STg mouse, which expresses an endothelial Cx40 mutant that permits electric, but not chemical transfer through gap junctions.…”

Minding the Gap

“…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).…”

“…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.…”