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Abstract: TH-OR25

Cross-Talk Between Epithelial Sodium Channel and Basolateral Kir4.1/Kir5.1 Channels in the Cortical Collecting Duct

Session Information

Category: Fluid, Electrolyte, and Acid-Base Disorders

  • 901 Fluid, Electrolyte, and Acid-Base Disorders: Basic

Authors

  • Palygin, Oleg, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Isaeva, Elena, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Levchenko, Vladislav, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Denton, Jerod S., Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Staruschenko, Alexander, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
Background

The growing body of evidence suggest that inwardly rectifying K+ (Kir) channels located on the basolateral membrane of epithelial cells in the distal nephron play a crucial role in K+ handling and blood pressure control, making these channels attractive targets for the treatment of hypertension. The purpose of the present study was to determine how the inhibition of basolateral Kir4.1 homomeric or Kir4.1/Kir5.1 heteromeric K+ channels affects ENaC-mediated Na+ transport in the cortical collecting duct (CCD) principal cells.

Methods

Electrophysiological approaches were used to test the effect of fluoxetine, amitriptyline, and recently developed Kir4.1 inhibitor, VU0134992, on the activity of Kir4.1, Kir4.1/Kir5.1, and ENaC. Channel activity was recorded in CHO cells transfected with respective channel subunits, cultured polarized epithelial mCCDc11 cells, and native freshly isolated rat and human CCD tubules. To test the effect of pharmacological Kir4.1/Kir5.1 inhibition on electrolyte homeostasis in vivo, Dahl salt-sensitive rats were injected with amitriptyline (15 mg/kg/day).

Results

We found that inhibition of Kir4.1/Kir5.1, but not Kir4.1 channel, substantially suppresses both amiloride-sensitive ISC in mCCDc11 cells and single-channel ENaC activity in principal cells of rat and human CCD tubules. Furthermore, we demonstrate that i.p. injection of Kir4.1/Kir5.1 antagonist for three days leads to a significant drop in plasma K+ level, triggering sodium excretion, and diuresis.

Conclusion

These data uncover a putative mechanism underlying a renal control of blood electrolytes mediated by Kir4.1/Kir5.1 and introduce a new molecular target for the treatment of salt-sensitive hypertension.

Funding

  • NIDDK Support