Rationale and Objectives: 

Based on previous findings that deletion of the connexin40 coding DNA in mice leads to renin dependent hypertension, we have analyzed the functional consequences of a loss of function point mutation (A96S) in exon 2 of the connexin 40 (Cx40) gene that had been described in a patient suffering from atrial fibrillation.

Methods and Results: 

We have generated and analyzed mice carrying the A96S mutation in their connexin 40 gene. The mutated Cx40 protein was expressed in the kidney in a pattern very similar to the wildtype Cx40 protein. In particular, renin producing, mesangial and endothelial cells expressed the mutated Cx40 protein in the plasma membrane in a typical fashion. Homozygous Cx40A96 mice were hypertensive and had 6-fold elevated plasma renin concentrations. Basal renin mRNA levels were increased by 40% in comparison to controls. Renin expressing cells in homozygous Cx40A96S kidneys were ectopically located and the renal baroreceptor control of renin secretion from isolated kidneys was abolished. Treatment with low salt diet in combination with an ACE-inhibitor increased renin mRNA levels and plasma renin concentrations in Cx40A96S mice to similar levels as in wildtype mice, respectively. The number of renin producing cells also increased, however in ectopic periglomerular localization in Cx40A96 mice.

Conclusions: 

These findings suggest that loss-of-function mutations in the Cx40 gene of mice and probably men can lead to renin dependent hypertension. The underlying renin hypersecretion is probably due to impairment of the baroreceptor control of renin secretion which, in turn, is likely caused by the ectopic extravascular localization of renin secreting cells in the kidney.