Genetic loss-of-function defects of
connexin 40 in renal juxtaglomerular cells are associated with
renin-dependent
hypertension. The dysregulation of
renin secretion results from an intrarenal displacement of
renin cells and an interruption of the negative feedback control of
renin secretion by blood pressure. It is unknown whether this phenotype is secondary to developmental defects of juxtaglomerular
renin cells due to
connexin 40 malfunction, or whether acute functional defects of
connexin 40 in the normal adult kidney can also lead to a similar dysregulation of
renin secretion and
hypertension. To address this question, we generated mice with an inducible deletion of
connexin 40 in the adult kidney by crossing
connexin 40-floxed mice with mice harboring a ubiquitously expressed
tamoxifen-inducible
Cre recombinase.
Tamoxifen treatment in these mice strongly reduced
connexin 40 mRNA and
protein expression in the kidneys. These mice displayed persistent
hypertension with
renin expression shifted from the media layer of afferent arterioles to juxtaglomerular periglomerular cells. Control of
renin secretion by the perfusion pressure was abolished in vitro, whereas in vivo plasma
renin concentrations were increased. Thus, interruption of the
connexin 40 gene in the adult kidney produced very similar changes in the
renin system as had embryonic deletion. Hence, impairments of
connexin 40 function in the normal adult kidney can cause
renin-dependent
hypertension.