The kidneys play a central role in the regulation of blood pressure by both controlling the salt and water homeostasis of the body and by releasing renin from the renin producing juxtaglomerular cells (JG cells). JG cells are located in the media layer of the afferent arterioles and are intensely coupled to themselves as well as to the neighbouring endothelial, smooth muscle and mesangial cells by gap junctions. Gap junctions are composed of two hemichannels that are assembled by six connexins each. Connexins comprise a family of at least 20 different transmembrane proteins in mice and 21 in humans. JG cells of adult mice express three of the four classical vascular connexins, namely connexin40 (Cx40), connexin37 (Cx37) and connexin43 (Cx43), while they do not express Cx45.

Since Cx40 is the most abundant connexin in JG cells and Cx40 knockout mice are hypertensive, the functional role of Cx40 in the regulation of the renin system has been studied in some detail.

Cx40 knockout mice (Cx40 -/-) have very high levels of plasma renin concentration (PRC) and renal renin gene expression suggesting the existence of a renin dependent form of hypertension in these mice. However, blockade of the renin-angiotensin-system by ACE-inhibitors does not completely normalize hypertension, indicating that additional factors contribute to the elevated arterial blood pressure. Detailed in vivo and in vitro analysis of the renin system in Cx40-/- revealed that the classical negative feedback control of renin synthesis and secretion by the blood pressure is absent in Cx40-/-. While an experimental renal artery stenosis markedly elevated plasma renin concentration (PRC) and systolic blood pressure in wildtype mice, these responses were absent in Cx40-/- mice. Furthermore, the inhibition of renin release by angiotensinII, forming another important feedback loop controlling the renin system, was markedly attenuated in the absence of Cx40. The drastic phenotype of Cx40-/- mice suggested that Cx40 has unique functions in JG cells. In order to test for this assumption, regulation of renin release was investigated in mice in which the coding sequence for Cx40 had been replaced by that for Cx45 (Cx40KI45). Accordingly JG cells of Cx40KI45 do not express Cx40 but instead Cx45, a connexin with different biophysical properties. Interestingly, the inhibitor effects of blood pressure and angiotensinII on renin release are completely restored in Cx40KI45 mice. Accordingly, PRC and renin gene expression is normal in Cx40KI45 compared to wildtypes. Although this normalization of PRC is accompanied by an almost complete normalization of arterial hypertension, blood pressure of Cx40KI45 mice is still slightly elevated compared to wildtypes. Therefore, these data corroborate the conclusion that Cx40 controls blood pressure to a large part by its critical role in the regulation of renin release but that additional functions of Cx40 contribute to blood pressure control.