Ablation of Potassium-Chloride Cotransporter Type 3 (Kcc3) in Mouse Causes Multiple Cardiovascular Defects and Isosmotic Polyuria

PLoS One. 2016 May 11;11(5):e0154398. doi: 10.1371/journal.pone.0154398. eCollection 2016.

Abstract

Inactivation of Kcc3 in a mixed 129/Sv×C57BL/6 mouse background has been previously found to increase systemic blood pressure (BP) through presumed neurogenic mechanisms. Yet, while this background is generally not considered ideal to investigate the cardiovascular system, KCC3 is also expressed in the arterial wall and proximal nephron. In the current study, the effects of Kcc3 ablation was investigated in a pure rather than mixed C57BL/6J background under regular- and high-salt diets to determine whether they could be mediated through vasculogenic and nephrogenic mechanisms. Aortas were also assessed for reactivity to pharmacological agents while isolated from the influence of sympathetic ganglia. This approach led to the identification of unforeseen abnormalities such as lower pulse pressure, heart rate, aortic reactivity and aortic wall thickness, but higher diastolic BP, left ventricular mass and urinary output in the absence of increased catecholamine levels. Salt loading also led systolic BP to be higher, but to no further changes in hemodynamic parameters. Importantly, aortic vascular smooth muscle cells and cardiomyocytes were both found to express KCC3 abundantly in heterozygous mice. Hence, Kcc3 inactivation in our model caused systemic vascular resistance and ventricular mass to increase while preventing extracellular fluid volume to accumulate. Given that it also affected the physiological properties of aortas in vitro, vasculogenic mechanisms could therefore account for a number of the hemodynamic abnormalities observed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta, Thoracic / metabolism
  • Aorta, Thoracic / physiopathology
  • Blood Pressure
  • Cardiovascular Diseases / blood
  • Cardiovascular Diseases / complications*
  • Cardiovascular Diseases / metabolism*
  • Cardiovascular Diseases / physiopathology
  • Gene Deletion*
  • Heart / physiopathology
  • Heart Function Tests
  • Hemodynamics
  • Hormones / metabolism
  • Kidney Function Tests
  • Lipids / blood
  • Mice, Inbred C57BL
  • Osmosis*
  • Polyuria / complications*
  • Polyuria / metabolism*
  • Polyuria / physiopathology
  • Sodium / metabolism
  • Symporters / metabolism*
  • Transcriptome / genetics

Substances

  • Hormones
  • Lipids
  • Slc12a6 protein, mouse
  • Symporters
  • Sodium

Grant support

Funding for this work came from Canada Foundation for Innovation (CFI); Canadian Institutes of Health Research (CIHR) [grant numbers: IC087830 and IC090498]; Kidney Foundation of Canada. Mister Alexandre P. Garneau was supported through a Master’s Training Award from the Fonds de recherche du Québec – Santé [award number 22593]. Dr. Paul Isenring holds a CFI-CIHR research chair in molecular physiology.