Impairment of the Vascular KATP Channel Imposes Fatal Susceptibility to Experimental Diabetes Due to Multi-Organ Injuries

J Cell Physiol. 2015 Dec;230(12):2915-26. doi: 10.1002/jcp.25003.

Abstract

The vascular isoform of ATP-sensitive K(+) (KATP ) channels regulates blood flow to all organs. The KATP channel is strongly inhibited by reactive oxygen and carbonyl species produced in diabetic tissue inflammation. To address how such channel inhibition impacts vascular regulation as well as tissue viability, we performed studies in experimental diabetic mice. Strikingly, we found that knockout of the Kcnj8 encoding Kir6.1 subunit (Kcnj8-KO) caused mice to be fatally susceptible to diabetes. Organ perfusion studies suggested that the lack of this vascular K(+) channel handicapped activity-dependent vasodilation, leading to hypoperfusion, tissue hypoxia, and multi-organ failure. Morphologically, Kcnj8-KO mice showed greater inflammatory cell infiltration, higher levels of expression of inflammation indicator proteins, more severe cell apoptosis, and worse tissue disruptions. These were observed in the kidney, liver, and heart under diabetic condition in parallel comparison to tissues from WT mice. Patch clamping and molecular studies showed that the KATP channel was S-glutathionylated in experimental diabetes contributing to the inhibition of channel activity as well as the reduced arterial responses to vasodilators. These results suggest that the vascular KATP channel is organ protective in diabetic condition, and since the channel is suppressed by diabetic oxidative stress, therapeutical interventions to the maintenance of functional KATP channels may help to lower or prevent diabetic organ dysfunction.

Publication types

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

MeSH terms

  • Animals
  • Blood Vessels / metabolism*
  • Blood Vessels / physiopathology
  • Diabetes Mellitus, Experimental / chemically induced*
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / physiopathology
  • Disease Susceptibility
  • Glutathione / metabolism
  • Hemodynamics*
  • Hypoxia / etiology
  • Hypoxia / metabolism
  • Hypoxia / physiopathology
  • KATP Channels / deficiency*
  • KATP Channels / genetics
  • Male
  • Membrane Potentials
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiple Organ Failure / etiology*
  • Multiple Organ Failure / genetics
  • Multiple Organ Failure / metabolism
  • Multiple Organ Failure / physiopathology
  • Multiple Organ Failure / prevention & control
  • Oxidative Stress
  • Regional Blood Flow
  • Signal Transduction
  • Streptozocin*
  • Vasodilation

Substances

  • KATP Channels
  • uK-ATP-1 potassium channel
  • Streptozocin
  • Glutathione