Xu Biyang, Levchenko Vladislav, Zietara Adrian, Fan Sarah, Klemens Christine A, Staruschenko Alexander
Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida.
Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida; Hypertension and Kidney Research Center, University of South Florida, Tampa, Florida.
Am J Pathol. 2025 Jan;195(1):115-125. doi: 10.1016/j.ajpath.2024.09.005. Epub 2024 Sep 26.
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 K5.1 plays an essential role in maintaining resting membrane potential. Patients with loss-of-function mutations in the KCNJ16 gene, which encodes K5.1, may have 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) to investigate how the deletion of K5.1 affects the regulation of acid-base balance in salt-sensitive hypertension. SS rats displayed metabolic acidosis under a normal salt diet. Further analysis using RNA sequencing and Western blot analyses showed unchanged expression of proteins responsible for ammonia metabolism in the kidney of SS 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 K5.1 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.
维持酸碱平衡对于正常生理功能至关重要。肾脏对于通过维持全身碳酸氢盐浓度来调节酸碱平衡必不可少。慢性代谢性酸中毒是慢性肾脏病的一个独立危险因素。肾脏内向整流钾通道K5.1在维持静息膜电位中起重要作用。编码K5.1的KCNJ16基因功能丧失突变的患者可能患有伴有低钾血症、失盐和听力丧失的肾小管病。重要的是，这些突变也会破坏酸碱平衡，尤其会导致代谢性酸中毒。本研究旨在使用敲除Kcnj16基因的 Dahl 盐敏感大鼠（SS大鼠）来研究K5.1的缺失如何影响盐敏感性高血压中酸碱平衡的调节。SS大鼠在正常盐饮食下表现出代谢性酸中毒。使用RNA测序和蛋白质印迹分析的进一步分析表明，尽管观察到酸中毒，但SS大鼠肾脏中负责氨代谢的蛋白质表达未发生变化。然而，碳酸氢盐转运体NBCe1的表达显著增加，而pendrin的表达则显著降低。总之，当前研究表明，K5.1的缺失损害了肾脏中氨代谢对代谢性酸中毒反应的敏感性，这为开发针对低钾血症和酸碱异常病症的潜在治疗方法提供了机制性见解。
