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Altered myogenic vasoconstriction and regulation of whole kidney blood flow in the ASIC2 knockout mouse

Am J Physiol Renal Physiol. 2015 Feb 15;308(4):F339-48. doi: 10.1152/ajprenal.00572.2014. Epub 2014 Dec 17.

Abstract

Previous studies from our laboratory have suggested that degenerin proteins contribute to myogenic constriction, a mechanism of blood flow regulation and protection against pressure-dependent organ injury, in renal vessels. The goal of the present study was to determine the importance of one family member, acid-sensing ion channel 2 (ASIC2), in myogenic constriction of renal interlobar arteries, myogenic regulation of whole kidney blood flow, renal injury, and blood pressure using ASIC2(+/+), ASIC2(+/-), and ASIC2(-/-) mice. Myogenic constriction in renal interlobar arteries was impaired in ASIC2(+/-) and ASIC2(-/-) mice, whereas constriction to KCl/phenylephrine was unchanged. Correction of whole kidney renal vascular resistance (RVR) during the first 5 s after a 10- to 20-mmHg step increase in perfusion pressure, a timeframe associated with myogenic-mediated correction of RVR, was slowed (4.2 ± 0.9, 0.3 ± 0.7, and 2.4 ± 0.3 resistance units/s in ASIC2(+/+), ASIC2(+/-), and ASIC2(-/-) mice). Although modest reductions in function were observed in ASIC2(-/-) mice, greater reductions were observed in ASIC2(+/-) mice, which may be explained by protein-protein interactions of ASIC2 with other degenerins. Isolated glomeruli from ASIC2(+/-) and ASIC2(-/-) mice had modest alterations in the expression of inflammation and injury markers (transforming growth factor-β, mouse anti-target of antiproliferative antibody-1, and nephrin), whereas ASIC2(+/-) mice had an increase in the remodeling marker collagen type III. Consistent with a more severe loss of function, mean arterial pressure was increased in ASIC2(+/-) mice (131 ± 3 mmHg) but not in ASIC2(-/-) mice (122 ± 3 vs. 117 ± 2 mmHg in ASIC2(+/+) mice). These results suggest that ASIC2 contributes to transduction of the renal myogenic response and are consistent with the protective role of myogenic constriction against renal injury and hypertension.

Keywords: acid-sensing ion channel 2; degenerin; pressure-induced constriction; renal injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Sensing Ion Channels / deficiency*
  • Acid Sensing Ion Channels / genetics
  • Animals
  • Arterial Pressure
  • Biomarkers / metabolism
  • Collagen Type III / metabolism
  • Dose-Response Relationship, Drug
  • Female
  • Genotype
  • Hypertension / genetics
  • Hypertension / metabolism
  • Hypertension / physiopathology
  • Inflammation Mediators / metabolism
  • Kidney / blood supply*
  • Kidney Diseases / genetics
  • Kidney Diseases / metabolism
  • Kidney Diseases / physiopathology
  • Male
  • Mechanotransduction, Cellular
  • Mice, Knockout
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / metabolism*
  • Muscle, Smooth, Vascular / physiopathology
  • Phenotype
  • Renal Artery / drug effects
  • Renal Artery / metabolism
  • Renal Circulation* / drug effects
  • Time Factors
  • Vasoconstriction* / drug effects
  • Vasoconstrictor Agents / pharmacology

Substances

  • ASIC2 protein, mouse
  • Acid Sensing Ion Channels
  • Biomarkers
  • Collagen Type III
  • Inflammation Mediators
  • Vasoconstrictor Agents