Role of Kir5.1 (Kcnj16) Channels in Regulating Renal Ammonia Metabolism during Metabolic Acidosis in Dahl Salt-Sensitive Rats.

Abstract

Maintaining acid-base homeostasis is critical for normal physiological function. The kidneys are essential for regulating acid-base homeostasis through maintaining systemic bicarbonate concentration. Chronic metabolic acidosis is an independent risk factor for chronic kidney diseases. Renal inwardly rectifying potassium channel K_ir5.1 plays an essential role in maintaining resting membrane potential. Patients with loss-of-function mutations in the KCNJ16 gene, which encodes K_ir5.1, reveal tubulopathy with hypokalemia, salt wasting, and hearing loss. Importantly, these mutations also disrupt acid-base balance, particularly causing metabolic acidosis. This study aimed to use Dahl salt-sensitive rats with a knockout of the Kcnj16 gene (SS^Kcnj16-/-) to investigate how the deletion of K_ir5.1 affects the regulation of acid-base balance in salt-sensitive hypertension. Results indicated that SS^Kcnj16-/- rats displayed metabolic acidosis under a normal salt diet. Further analysis using RNA sequencing and Western blot analysis showed unchanged expression of proteins responsible for ammonia metabolism in the kidney of SS^Kcnj16-/- rats despite observed acidosis. However, there was a significant increase in the expression of bicarbonate transporter NBCe1, where there was a significant decrease in pendrin. In conclusion, the current study demonstrated that the loss of K_ir5.1 impairs the sensitivity of ammonia metabolism in the kidney in response to metabolic acidosis, which provides mechanistic insights into developing potential therapeutics for conditions involving hypokalemia and acid-base abnormalities.