Restoration of Connexin 40 (Cx40) in Renin-Producing Cells Reduces the Hypertension of Cx40 Null Mice

Abstract

Abstract-Connexin 40 (Cx40) is expressed by the renin-producing cells (RSCs) of the kidneys and the endothelial cells of blood vessels. Cx40 null mice (Cx40 −/− ) feature a much increased renin synthesis and secretion, which results in chronic hypertension, and also display an altered endothelium-dependent relaxation of the aorta because of reduced eNOS levels and nitric oxide production. To discriminate the effect of Cx40 in renin secretion and vascular signaling, we targeted Cx40 to either the RSCs or the endothelial cells of Cx40 null mice. When compared with Cx40 −/− controls, the animals expressing Cx40 in RSCs were less hypertensive and featured reduced renin levels, still numerous RSCs outside the wall of the afferent arterioles. In contrast, mice expressing Cx40 in the endothelial cells were as hypertensive as Cx40 −/− mice, in spite of control levels of Cx37 and eNOS. Our data show that blood pressure is improved by restoration of Cx40 expression in RSCs but not in endothelial cells, stressing the prominent role of renin in the mouse hypertension linked to

Interplay Between Connexin40 and Nitric Oxide Signaling During Hypertension

“…8 In this model, the normal levels of eNOS presumably ensure a normal arterial relaxation, contributing to counteract the increased blood pressure resulting from the loss of Cx40 in the renin-secreting cells. 8 The association of volume-and renin-dependent hypertension increased by ≈10% the blood pressure of Cx40−/− mice. Under these conditions, we observed an increased phosphorylation of eNOS which by enhancing the activity of the enzyme 33,34 could mitigate the reduced interaction between Cx and eNOS, resulting from the nil (Cx40) to lower (Cx37) levels of the former proteins.…”

“…[4][5][6][7][8] These proteins form channels for the communication of ECs and SMCs, which is needed to coordinate vasoconstriction and vasodilation along the vessels.9 ECs predominantly express Cx37 and Cx40, [5][6][7] whereas SMCs mostly express Cx43 and Cx45. 5,6,10 Mice lacking Cx40 feature hypertension 4,6,11,12 because of increased secretion of renin 4,13 and reduced relaxation of peripheral vessels.…”

“…The resulting vessel adaptation consistently induced the expression of Cx37 in SMCs by a mechanism which remains to be addressed. This change could reflect a loosening of the correlation between Cx40 and Cx37 expression 6,8 or an altered phenotype of the SMCs which, after prolonged hypertension, penetrate the intimal layer of vessels. [1][2][3]9,10 Second, we focused on the relationship between Cxs and eNOS, 5,8,15 a key EC enzyme for the production of NO, which relaxes SMCs, thus contributing to the control of blood pressure.…”

“…This change could reflect a loosening of the correlation between Cx40 and Cx37 expression 6,8 or an altered phenotype of the SMCs which, after prolonged hypertension, penetrate the intimal layer of vessels. [1][2][3]9,10 Second, we focused on the relationship between Cxs and eNOS, 5,8,15 a key EC enzyme for the production of NO, which relaxes SMCs, thus contributing to the control of blood pressure. 5,14,22,25 We now show that volume-dependent hypertension promotes the interaction of Cx40 and Cx37 with eNOS and that this interaction results in increased release of NO.…”

“…[4][5][6][7][8] These proteins form channels for the communication of ECs and SMCs, which is needed to coordinate vasoconstriction and vasodilation along the vessels.…”