The connexin 40 A96S mutation causes renin-dependent hypertension

J Am Soc Nephrol. 2011 Jun;22(6):1031-40. doi: 10.1681/ASN.2010101047. Epub 2011 May 19.

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 renin-secreting cells in the kidney likely impairs the pressure-mediated inhibition of renin secretion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Animals
  • Connexins / genetics*
  • Diet, Sodium-Restricted
  • Disease Models, Animal
  • Female
  • Gap Junctions / physiology
  • HeLa Cells
  • Humans
  • Hypertension / genetics*
  • Hypertension / physiopathology*
  • Hypertension / therapy
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation / genetics*
  • Renin / physiology*
  • Transfection
  • Treatment Outcome

Substances

  • Angiotensin-Converting Enzyme Inhibitors
  • Connexins
  • connexin 40
  • Renin