Substitution of connexin40 with connexin45 prevents hyperreninemia and attenuates hypertension.
Connexins (Cxs) are a family of transmembrane proteins that form gap junctions with unique and redundant biophysical functions. Juxtaglomerular cells express Cx40, which is crucial to the control of renin secretion by blood pressure and angiotensin II, and mice that lack Cx40 have high plasma renin and hypertension. To examine whether normal juxtaglomerular cell function depends on the unique properties of Cx40, we measured renin release in mice where the coding sequence for Cx40 was replaced by that for Cx45, using the knock-in method. We first found that the knock-in strategy indeed resulted in expression of Cx45 but not Cx40 in the juxtaglomerular cells of these mice. The plasma renin concentration of the knock-in mice was similar to that in wild-type mice. The high blood pressure of the Cx40 knockout mice was significantly reduced when Cx45 was knocked into the locus but remained mildly elevated compared to wild-type mice. Blockade of angiotensin II formation by enalapril increased the plasma renin concentration in wild-type and the Cx45 knock-in mice but not in the Cx40 knockout mice. Infusion of angiotensin II into isolated perfused kidneys results in decreased renin release, a phenomenon that was attenuated in the Cx40 knockout mice. However, in the Cx45 knock-in mice, angiotensin II suppressed renin release similar to its effect in wild type mice. Unilateral renal artery stenosis increased the plasma renin concentration and blood pressure in both the wild-type and the Cx45 knock-in mice but not in the Cx40 knockout mice. Since Cx40 can be replaced by Cx45, a connexin with a significantly lower conductivity, we suggest that the regulation of renin release is not dependent on the unique electrical properties of these channel proteins.
Schweda
Frank
F
Institute of Physiology, University of Regensburg, Regensburg, Germany. frank.schweda@klinik.uni-regensburg.de
Kurtz
Lisa
L
de Wit
Cor
C
Janssen-Bienhold
Ulrike
U
Kurtz
Armin
A
Wagner
Charlotte
C
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D017630:Connexins / Q000172:deficiency* / Q000235:genetics*; D055879:Gene Knock-In Techniques; D015316:Genetic Therapy; D006973:Hypertension / Q000628:therapy*; D007606:Juxtaglomerular Apparatus / Q000166:cytology; D007668:Kidney / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012083:Renin / Q000097:blood*; D000097003:Gap Junction alpha-5 Protein
D000804:Angiotensin II; D017630:Connexins; D012083:Renin; D000097003:Gap Junction alpha-5 Protein; C082920:connexin 45