Physiology and Health, Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.
Zoophysiology, Department of Biology, Aarhus University, 8000 Aarhus, Denmark.
Proc Natl Acad Sci U S A. 2022 Feb 22;119(8). doi: 10.1073/pnas.2116836119.
The lungs and kidneys are pivotal organs in the regulation of body acid-base homeostasis. In cystic fibrosis (CF), the impaired renal ability to excrete an excess amount of HCO into the urine leads to metabolic alkalosis [P. Berg et al., 31, 1711-1727 (2020); F. Al-Ghimlas, M. E. Faughnan, E. Tullis, 6, 59-62 (2012)]. This is caused by defective HCO secretion in the β-intercalated cells of the collecting duct that requires both the cystic fibrosis transmembrane conductance regulator (CFTR) and pendrin for normal function [P. Berg et al., 31, 1711-1727 (2020)]. We studied the ventilatory consequences of acute oral base loading in normal, pendrin knockout (KO), and CFTR KO mice. In wild-type mice, oral base loading induced a dose-dependent metabolic alkalosis, fast urinary removal of base, and a moderate base load did not perturb ventilation. In contrast, CFTR and pendrin KO mice, which are unable to rapidly excrete excess base into the urine, developed a marked and transient depression of ventilation when subjected to the same base load. Therefore, swift renal base elimination in response to an acute oral base load is a necessary physiological function to avoid ventilatory depression. The transient urinary alkalization in the postprandial state is suggested to have evolved for proactive avoidance of hypoventilation. In CF, metabolic alkalosis may contribute to the commonly reduced lung function via a suppression of ventilatory drive.
肺和肾是调节体内酸碱平衡的关键器官。在囊性纤维化（CF）中，肾脏排泄过多 HCO 的能力受损，导致代谢性碱中毒[P. Berg 等人，31，1711-1727（2020）；F. Al-Ghimlas、M. E. Faughnan、E. Tullis，6，59-62（2012）]。这是由于β-闰细胞中 HCO 的分泌缺陷所致，该分泌需要囊性纤维化跨膜电导调节因子（CFTR）和 pendrin 才能正常发挥作用[P. Berg 等人，31，1711-1727（2020）]。我们研究了急性口服碱负荷对正常、pendrin 敲除（KO）和 CFTR KO 小鼠的通气后果。在野生型小鼠中，口服碱负荷引起剂量依赖性代谢性碱中毒、快速尿碱排泄，且适度碱负荷不会扰乱通气。相比之下，CFTR 和 pendrin KO 小鼠由于不能迅速将多余的碱排泄到尿液中，当受到相同的碱负荷时，会出现明显而短暂的通气抑制。因此，迅速的肾脏碱排泄以响应急性口服碱负荷是避免通气抑制的必要生理功能。餐后短暂的尿碱化可能是为了主动避免通气不足而进化而来的。在 CF 中，代谢性碱中毒可能通过抑制通气驱动来导致肺功能普遍降低。
