Center for Experimental Medicine, Institute of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Department of Biomedicine, Physiology, Health, Aarhus University, Aarhus, Denmark.
Nat Commun. 2023 May 26;14(1):3051. doi: 10.1038/s41467-023-38562-x.
The kidney plays a key role in the correction of systemic acid-base imbalances. Central for this regulation are the intercalated cells in the distal nephron, which secrete acid or base into the urine. How these cells sense acid-base disturbances is a long-standing question. Intercalated cells exclusively express the Na-dependent Cl/HCO exchanger AE4 (Slc4a9). Here we show that AE4-deficient mice exhibit a major dysregulation of acid-base balance. By combining molecular, imaging, biochemical and integrative approaches, we demonstrate that AE4-deficient mice are unable to sense and appropriately correct metabolic alkalosis and acidosis. Mechanistically, a lack of adaptive base secretion via the Cl/HCO exchanger pendrin (Slc26a4) is the key cellular cause of this derailment. Our findings identify AE4 as an essential part of the renal sensing mechanism for changes in acid-base status.
肾脏在纠正全身酸碱失衡中起着关键作用。这种调节的核心是远曲小管中的闰细胞，它们将酸或碱分泌到尿液中。这些细胞如何感知酸碱紊乱是一个长期存在的问题。闰细胞专门表达 Na 依赖性 Cl/HCO3 交换体 AE4（Slc4a9）。在这里，我们发现 AE4 缺陷小鼠表现出酸碱平衡的严重失调。通过结合分子、成像、生化和综合方法，我们证明 AE4 缺陷小鼠无法感知和适当纠正代谢性碱中毒和酸中毒。从机制上讲，Cl/HCO3 交换体 pendrin（Slc26a4）缺乏适应性的基础分泌是这种脱轨的关键细胞原因。我们的研究结果表明，AE4 是肾脏感知酸碱状态变化的感应机制的重要组成部分。
