The connexin40 A96S mutation causes renin-dependent hypertension

Indra Lübkemeier, Katharina Machura, Lisa Kurtz, Björn Neubauer, Radek Dobrowolski, Frank Schweda, Charlotte Wagner, Klaus Willecke, Armin Kurtz

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Deletion of the gap-junction - forming protein connexin40 leads to renin-dependent hypertension in mice, but whether observed human variants in connexin40, such as A96S, promote hypertension is unknown. Here, we generated mice with the A96S variant in the mouse connexin40 gene. Although mice homozygous for the A96S mutations had normal expression patterns of connexin40 in the kidney, they were hypertensive, had sixfold higher plasma renin concentrations, and had 40% higher levels of renin mRNA than controls. Renin-expressing cells were aberrantly located outside the media layer of afferent arterioles, and increased renal perfusion pressure did not inhibit renin secretion from kidneys isolated from homozygous A96S mice. Treatment with a low-salt diet in combination with an ACE inhibitor increased renin mRNA levels, plasma renin concentrations, and the number of aberrantly localized renin-producing cells. Taken together, these findings suggest that the A96S mutation in connexin40 leads to renin-dependent hypertension in mice. Modulation of renin secretion by BP critically depends on functional connexin40; with the A96S mutation, the aberrant extravascular localization of reninsecreting cells in the kidney likely impairs the pressure-mediated inhibition of renin secretion.

Original languageEnglish (US)
Pages (from-to)1031-1040
Number of pages10
JournalJournal of the American Society of Nephrology
Volume22
Issue number6
DOIs
StatePublished - Jun 1 2011

ASJC Scopus subject areas

  • Nephrology

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    Lübkemeier, I., Machura, K., Kurtz, L., Neubauer, B., Dobrowolski, R., Schweda, F., Wagner, C., Willecke, K., & Kurtz, A. (2011). The connexin40 A96S mutation causes renin-dependent hypertension. Journal of the American Society of Nephrology, 22(6), 1031-1040. https://doi.org/10.1681/ASN.2010101047