Kidney Week

Abstract: FR-PO579

Kir4.1/Kir5.1 Channel Inhibition Acutely Ameliorates Hyperkalemia in Male Rats with Reduced Kidney Function

Session Information

• Fluid, Electrolyte, and Acid-Base Disorders: Basic
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Fluid, Electrolytes, and Acid-Base Disorders

• 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic

Authors

• Alexander, Sati Amrita, Augusta University, Augusta, Georgia, United States

Sati Amrita Alexander

• Tubalinal, Bianca, Augusta University, Augusta, Georgia, United States

Bianca Tubalinal

• Coleman, Kathleen A., Augusta University, Augusta, Georgia, United States

Kathleen A. Coleman

• Nguyen, Jenny, Augusta University, Augusta, Georgia, United States

Jenny Nguyen

• Palygin, Oleg, Medical University of South Carolina, Charleston, South Carolina, United States

Oleg Palygin, PhD

• Mamenko, Mykola, Augusta University, Augusta, Georgia, United States

Mykola Mamenko, PhD

Background

Patients with advanced chronic kidney disease (CKD) can develop hyperkalemia, a life-threatening condition causing cardiac arrhythmia, paralysis, and death. Basic science lacks a suitable animal model that accurately reflects hyperkalemic states observed in patients with CKD, and there is an unmet need for novel pharmacological approaches managing hyperkalemia in CKD, as current interventions are fraught with adverse effects. Inhibition of the renal basolateral K⁺ channels, like Kir4.1 and Kir4.1/5.1, does not rely on glomerular filtration and is an attractive target to treat hyperkalemia in patients with advanced CKD. Genetic deletion of either Kir4.1 or Kir5.1 protein leads to hypokalemia and salt wasting. Here, we test the hypothesis that pharmacological blockade of these channels provides an effective treatment against hyperkalemia.

Methods

First, we established a rat model of chronic hyperkalemia. To do this, ten 35-week-old Sprague-Dawley rats of both sexes underwent 5/6-nephrectomy moderately elevating serum K⁺ levels to 5.3±0.3 mEq/L in males and 5.0±0.5 mEq/L in females. Nephrectomized rats were placed on a 10% KCl diet for 7 days to achieve persistent hyperkalemia with serum K⁺ significantly increased to 6.9±1.1 mEq/L in males and 6.7±0.9 mEq/L in females. To assess the effect of Kir4.1 and Kir4.1/5.1 Kir channel inhibition on circulating potassium, a commercially available antagonist, VU0134992, was administered by oral gavage (100mg/kg) and serum K⁺ concentration was measured at 4 and 24 hours after the treatment.

Results

In males, serum K⁺ concentration was significantly reduced to 6.0±0.6 mEq/L and 5.8±0.8 mEq/L at 4 and 24 hours after VU administration, respectively. In females administered with VU serum K⁺ remained comparable to pre-treatment levels at 6.5±0.6 mEq/L and 7.4±1.2 mEq/L at 4 and 24 hours after the intervention.

Conclusion

Our study establishes 5/6 nephrectomized rats on a 10% KCl diet as a model of chronic hyperkalemia. Inhibition of Kir4.1 and Kir4.1/5.1 Kir channels acutely reduces serum K⁺ levels in hyperkalemic male rats with reduced renal function, but not in females.

Funding

• NIDDK Support