Connexin 40 is dispensable for vascular renin cell recruitment but is indispensable for vascular baroreceptor control of renin secretion

Abstract

Defects of the gap junction protein connexin 40 (Cx40) in renin-secreting cells (RSCs) of the kidney lead to a shift of the localization of RSCs from the media layer of afferent arterioles to the periglomerular interstitium. The dislocation of RSCs goes in parallel with elevated plasma renin levels, impaired pressure control of renin secretion, and hypertension. The reasons for the extravascular shift of RSCs and the blunted pressure regulation of renin secretion caused by the absence of Cx40 are still unclear. We have therefore addressed the question if Cx40 is essential for the metaplastic transformation of preglomerular vascular smooth muscle cells (SMCs) into RSCs and if Cx40 is essential for the pressure control of renin secretion from RSCs located in the media layer of afferent arterioles. For our study, we used mice lacking the angiotensin II type 1A (AT1A) receptors, which display a prominent and reversible salt-sensitive metaplastic transformation of SMCs into RSCs. This mouse line was crossed with Cx40-deficient mice to obtain AT1A and Cx40 double deleted mice. The kidneys of AT1A (-/-)Cx40(-/-) mice kept on normal salt (0.3 %) displayed RSCs both in the inner media layer of preglomerular vessels and in the periglomerular interstitium. In contrast to hypotensive AT1A (-/-) (mean bp syst 112 mmHg) and hypertensive Cx40(-/-) (mean bp syst 160 mmHg) mice AT1A (-/-)Cx40(-/-) mice were normotensive(mean bp syst 130 mmHg). Pressure regulation of renin secretion from isolated kidneys was normal in AT1A (-/-) mice, but was absent in AT1A (-/-)Cx40(-/-) mice alike in Cx40(-/-) mice. Low-salt diet (0.02 %) increased RSC numbers in the media layer, whilst high-salt diet (4 %) caused disappearance of RSCs in the media layer but not in the periglomerular interstitium. Blood pressure was clearly salt sensitive both in AT1A (-/-) and in AT1A (-/-)Cx40(-/-) mice but was shifted to higher pressure values in the latter genotype. Our data indicate that Cx40 is not a requirement for intramural vascular localization of RSCs nor for reversible metaplastic transformation of SMCs into RSCs. Therefore, the ectopic localization of RSCs in Cx40(-/-) kidneys is more likely due to a disturbed intercellular communication rather than being the result of chronic overactivation of the renin-angiotensin-aldosterone system or hypertension. Moreover, our findings suggest that Cx40 is a requirement for the pressure control of renin secretion irrespective of the localization of RSCs.

Connexins in the control of vasomotor function

“…Additionally, Cx40 has been found to play other important roles. In the kidney, Cx40 KO is accompanied by an impaired pressure‐dependent renin release as well as by reduced renal autoregulation and tubuloglomerular feedback …”

Connexin‐mediated cell communication in the kidney: A potential therapeutic target for future intervention of diabetic kidney disease?

“…Chronic changes in blood pressure necessitate recruitment of new renin‐secreting cells from transformed smooth muscle cells associated with the pre‐glomerular arterioles. This transformation is accompanied by increased expression of CX40 at the expense of CX45 (Machura et al., ). Enhanced CX40 expression is thought to increase cell‐to‐cell coupling between renin‐secreting cells and their neighbours, including endothelial, smooth muscle and mesangial cells (Machura et al., ).…”

“…This transformation is accompanied by increased expression of CX40 at the expense of CX45 (Machura et al., ). Enhanced CX40 expression is thought to increase cell‐to‐cell coupling between renin‐secreting cells and their neighbours, including endothelial, smooth muscle and mesangial cells (Machura et al., ). Loss of function defects in CX40 causes translocation of renin‐secreting cells from the media layer of the afferent arteriole into the periglomerular interstitium.…”

“…Reasons for the shift of renin‐secreting cells in the absence of CX40 and the subsequent loss of blood pressure regulation in response to enhanced renin secretion are unknown, but the work of Machura et al . (), suggests that re‐localisation of cells probably arises as a consequence of disrupted connexin‐mediated cell communication rather than enhanced activation of the renin angiotensinogen system (Machura et al., ). Moreover, recent work by Haefliger et al .…”

Analysis of the calcium paradox of renin secretion

“…Moreover, it appears that upon isolation of cells and disruption of cell-to-cell coupling, important features of calcium-regulated renin secretion get lost. In this context several studies showed that intercellular communication via Cx40-dependent gap junctions plays an important role in relaying the calcium-dependent inhibitor effects of angiotensin II and of intrarenal pressure on renin secretion (33,66,67).…”