Selective deletion of Connexin 40 in renin-producing cells impairs renal baroreceptor function and is associated with arterial hypertension

Abstract

Renin-producing juxtaglomerular cells are connected to each other and to endothelial cells of afferent arterioles by gap junctions containing Connexin 40 (Cx40), abundantly expressed by these two cell types. Here, we generated mice with cell-specific deletion of Cx40 in endothelial and in renin-producing cells, as its global deletion caused local dissociation of renin-producing cells from endothelial cells, renin hypersecretion, and hypertension. In mice lacking endothelial Cx40, the blood pressure, renin-producing cell distribution, and the control of renin secretion were similar to wild-type mice. In contrast, mice deficient for Cx40 in renin-producing cells were hypertensive and these cells were ectopically localized. Although plasma renin activity and kidney renin mRNA levels of these mice were not different from controls, the negative regulation of renin secretion by pressure was inverted to a positive feedback in kidneys lacking Cx40 in renin-producing cells. Thus, our findings show that endothelial Cx40 is not essential for the control of renin expression and/or release. Cx40 in renin-producing cells is required for their correct positioning in the juxtaglomerular area and the control of renin secretion by pressure.

Connections in chronic kidney disease: connexin 43 and connexin 37 interaction

“…Deletion of Cx40 in reninproducing but not in endothelial cells resulted in hyperreninemia and hypertension (17,30). Kurt et al (17) also reported that there is a "reciprocal expression of Cx40 and Cx45 during phenotypical changes in renin-secreting cells".…”

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.…”

“…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.…”

“…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.…”

“…Endothelial Cx40 is not required for recruitment or localization, as Tie2-Cre Cx40 fl/fl mice display appropriate renin cell localization and stimulated recruitment. 3 Thus, while proper localization and recruitment of renin cells require functional Cx40, these two processes appear to be regulated independently.…”