title: Inducible deletion of connexin 40 in adult mice causes hypertension and disrupts pressure control of renin secretion.
abstract: 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.
authors.affiliation: Department of Physiology, University of Regensburg, Regensburg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Gerl
authors.affiliation: Department of Physiology, University of Regensburg, Regensburg, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Vöckl
authors.affiliation: Department of Physiology, University of Regensburg, Regensburg, Germany.
authors.forename: Birgül
authors.initials: B
authors.lastname: Kurt
authors.affiliation: Department of Medical Physiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Toon A B
authors.initials: TA
authors.lastname: van Veen
authors.affiliation: Department of Physiology, University of Regensburg, Regensburg, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Kurtz
authors.affiliation: Department of Physiology, University of Regensburg, Regensburg, Germany.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Wagner
mesh_terms: D000818:Animals; D001483:Base Sequence; D001794:Blood Pressure / Q000235:genetics; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D025461:Feedback, Physiological; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology*; D019426:Integrases / Q000378:metabolism; D007606:Juxtaglomerular Apparatus / Q000378:metabolism; D008297:Male; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D012083:Renin / Q000097:blood / Q000378:metabolism*; D017384:Sequence Deletion; D013629:Tamoxifen; D000097003:Gap Junction alpha-5 Protein
chemical_list: D017630:Connexins; D019426:Integrases; D012333:RNA, Messenger; D012083:Renin; D013629:Tamoxifen; D000097003:Gap Junction alpha-5 Protein; C045073:Cre recombinase