Kidney Week

Abstract: SA-PO0483

Kir5.1 Deficiency and High-Salt Intake Impair Renal Acid-Base Balance in Dahl Salt-Sensitive Rats

Session Information

• Fluid, Electrolyte, and Acid-Base Disorders: Basic Research
  November 08, 2025 | 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

• Fan, Sarah, University of South Florida Morsani College of Medicine, Tampa, Florida, United States

Sarah Fan

• Xu, Biyang, University of South Florida Morsani College of Medicine, Tampa, Florida, United States

Biyang Xu, PhD

• Levchenko, Vladislav, University of South Florida Morsani College of Medicine, Tampa, Florida, United States

Vladislav Levchenko

• Zietara, Adrian, University of South Florida Morsani College of Medicine, Tampa, Florida, United States

Adrian Zietara, PhD

• Klemens, Christine Anne, University of South Florida Morsani College of Medicine, Tampa, Florida, United States

Christine Anne Klemens, PhD

• Staruschenko, Alexander, University of South Florida Morsani College of Medicine, Tampa, Florida, United States

Alexander Staruschenko, PhD, FASN

Background

Acid-base homeostasis is essential for normal physiological function. Previous studies have linked salt sensitivity in humans to abnormal acid-base regulation. Notably, patients with mutations in the KCNJ16 gene, which encodes the inwardly rectifying potassium channel K_ir5.1, display metabolic acidosis. However, the underlying mechanisms remain unclear. Here, we investigate renal handling of acid-base balance 1) under normal salt (0.4% NaCl, NS) and high salt (4% NaCl, HS) diets and 2) under K_ir5.1 deletion by comparing Dahl salt-sensitive wild-type rats to rats lacking K_ir5.1 (SS^WT vs SS^Kcnj16-/-).

Methods

To evaluate the HS diet's effects, 8-week-old male and female SS^WT rats were fed HS for 3 weeks, then given 0.28 M NH₄Cl with 1% sucrose in drinking water for 8 days. To evaluate the role of K_ir5.1 channels, 10-week-old male and female SS^Kcnj16-/- rats fed NS were similarly acid-loaded.

Results

Results indicated that before the acid-loading, the HS diet did not change the blood pH, HCO₃^- or urine pH of either male or female rats compared to the NS diet. However, the HS diet significantly decreased the urinary NH₄⁺ excretion in males (1.03 ± 0.27 mmol vs 2.17 ± 0.28 mmol; HS vs NS). During acid-loading, both sexes under HS showed impaired urinary NH₄⁺ excretion per decreased blood HCO₃^- compared to NS.

In SS^Kcnj16-/- rats, both sexes showed significantly lower baseline blood pH (females: 7.20 ± 0.01 vs. 7.31 ± 0.03; males: 7.14 ± 0.02 vs. 7.35 ± 0.02) and HCO₃^- concentrations (females: 16.3 ± 0.6 mM vs 22.6 ± 0.6 mM; males: 18.4 ± 0.7 mM vs 26.2 ± 0.6 mM) compared to SS^WT rats, with no change in urinary pH. Interestingly, urinary NH₄⁺ excretion and net acid excretion were significantly lower in male SS^Kcnj16-/- rats compared to SS^WT rats. Surprisingly, acid-loading triggered mortality in female but not male SS^Kcnj16-/- rats. Western blot analyses indicated that although the acid-loading significantly increased the expression of glutaminase-1 in both female and male SS^WT rats loaded with acid, such elevation was not observed in SS^Kcnj16-/- rats.

Conclusion

In summary, both the HS diet and lack of K_ir5.1 impaired renal acid-base regulation in salt-sensitive hypertension. Furthermore, the loss of K_ir5.1 blunted the sensitivity of renal ammonia metabolism to metabolic acidosis.

Funding

• NIDDK Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.202509yp1133