Kidney Week

Abstract: TH-OR25

Cross-Talk Between Epithelial Sodium Channel and Basolateral K_ir4.1/K_ir5.1 Channels in the Cortical Collecting Duct

Session Information

• Molecular Insights in Ion, Acid, and Water Handling
  October 22, 2020 | Location: Simulive
  Abstract Time: 05:00 PM - 07:00 PM

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

Oleg Palygin, PhD



My research is focused on ion channels and ion transport in the kidney, and I apply multiple sophisticated approaches to address unresolved questions of physiological mechanisms responsible for the regulation of renal function in health and disease. Today, a greater understanding has been achieved of the cellular and molecular mechanisms underlying renal function processes and how these processes may become disordered in chronic kidney disease states such as hypertension, polycystic kidney, and diabetes mellitus. My laboratory is interested in several aspects of the kidney: its ability to control and regulate body electrolytes, its vulnerability to genetically related mutations, oxidative stress, albuminuria, and the role that transport potassium channels, protease-activated receptors, and the purines like ATP play in these processes.

• Isaeva, Elena, Medical College of Wisconsin, Milwaukee, Wisconsin, United States

Elena Isaeva,

• Levchenko, Vladislav, Medical College of Wisconsin, Milwaukee, Wisconsin, United States

Vladislav Levchenko,

• Denton, Jerod S., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Jerod S. Denton,

• Staruschenko, Alexander, Medical College of Wisconsin, Milwaukee, Wisconsin, United States

Alexander Staruschenko,

Background

The growing body of evidence suggest that inwardly rectifying K⁺ (K_ir) 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 K_ir4.1 homomeric or K_ir4.1/K_ir5.1 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 K_ir4.1 inhibitor, VU0134992, on the activity of K_ir4.1, K_ir4.1/K_ir5.1, and ENaC. Channel activity was recorded in CHO cells transfected with respective channel subunits, cultured polarized epithelial mCCD_c11 cells, and native freshly isolated rat and human CCD tubules. To test the effect of pharmacological K_ir4.1/K_ir5.1 inhibition on electrolyte homeostasis in vivo, Dahl salt-sensitive rats were injected with amitriptyline (15 mg/kg/day).

Results

We found that inhibition of K_ir4.1/K_ir5.1, but not K_ir4.1 channel, substantially suppresses both amiloride-sensitive I_SC in mCCD_c11 cells and single-channel ENaC activity in principal cells of rat and human CCD tubules. Furthermore, we demonstrate that i.p. injection of K_ir4.1/K_ir5.1 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 K_ir4.1/K_ir5.1 and introduce a new molecular target for the treatment of salt-sensitive hypertension.

Funding

• NIDDK Support