Gilker Eva A, Xu Kui, Moss Fraser J, Boron Walter F
Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States.
Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States.
Am J Physiol Regul Integr Comp Physiol. 2025 Sep 1;329(3):R441-R458. doi: 10.1152/ajpregu.00088.2025. Epub 2025 Jul 18.
During systemic acid-base disturbances, the respiratory system modulates CO elimination, whereas the urinary system modulates H secretion-responses that tend to stabilize arterial pH (pH). Proximal tubules (PTs) are responsible for ∼80% of renal H secretion. Isolated PTs appear to sense and respond to acute changes in basolateral [CO] or [[Formula: see text]] using a mechanism that signals through apical angiotensin II AT receptors. In the present study, we examine the whole animal responses to both respiratory acidosis (RAc: ↑[CO] → ↓pH) and metabolic acidosis (MAc: ↓[[Formula: see text]] → ↓pH) in wild-type (WT) versus AT knockout (KO) mice. After catheterizing the carotid artery, we serially sample blood for arterial blood-gas analyses. We find that, in mice breathing 8% CO, pH reaches a nadir at ∼5 min, and begins to recover after ∼4 h, reaching its maximal value by ∼24 h. Surprisingly, we find that the KO of AT does not affect RAc compensation. During MAc (1% NHCl in drinking water), WT males exhibit only a small/insignificant fall in pH, whereas WT females exhibit a larger/significant pH decrease. In another sexual dimorphism, AT-KO males acidify on of MAc, but nearly recover by , whereas KO females exhibit either of two responses: ) adaptive, in which pH falls relatively little by and then recovers by , and ) maladaptive, in which pH falls at and remains depressed at . Thus, AT is crucial for defense against MAc in all but half the females, but not RAc. Here, for the first time, we report that the compensatory response to respiratory acidosis (RAc) in conscious mice concludes within 24 h. Interestingly, during the assessment of metabolic acidosis (MAc), we show that WT males are more adaptive than females, and observe two subpopulations of AT-KO females. From measurements of arterial pH, we conclude that AT is not necessary for the compensation to RAc, but is necessary in the response to MAc.
在全身性酸碱紊乱期间，呼吸系统调节二氧化碳的排出，而泌尿系统调节氢离子的分泌——这些反应倾向于稳定动脉血pH值。近端小管（PTs）负责肾脏约80%的氢离子分泌。分离的近端小管似乎利用一种通过顶端血管紧张素II AT受体发出信号的机制来感知并响应基底外侧二氧化碳或碳酸氢根离子的急性变化。在本研究中，我们检测了野生型（WT）与AT基因敲除（KO）小鼠对呼吸性酸中毒（RAc：二氧化碳增加→pH值降低）和代谢性酸中毒（MAc：碳酸氢根离子降低→pH值降低）的整体动物反应。在插入颈动脉导管后，我们连续采集血液进行动脉血气分析。我们发现，在吸入8%二氧化碳的小鼠中，pH值在约5分钟时达到最低点，并在约4小时后开始恢复，到约24小时时达到最大值。令人惊讶的是，我们发现AT基因敲除并不影响对呼吸性酸中毒的代偿。在代谢性酸中毒（饮用水中含1%氯化铵）期间，野生型雄性小鼠的pH值仅出现轻微/不显著下降，而野生型雌性小鼠的pH值则出现较大/显著下降。在另一种性别差异中，AT基因敲除的雄性小鼠在代谢性酸中毒开始时酸化，但在结束时几乎恢复，而基因敲除的雌性小鼠则表现出两种反应之一：1）适应性反应，即pH值在开始时下降相对较小，然后在结束时恢复；2）非适应性反应，即pH值在开始时下降，并在结束时仍处于较低水平。因此，除了一半的雌性小鼠外，AT对抵御代谢性酸中毒至关重要，但对呼吸性酸中毒则不然。在此，我们首次报告清醒小鼠对呼吸性酸中毒（RAc）的代偿反应在24小时内完成。有趣的是，在评估代谢性酸中毒（MAc）期间，我们发现野生型雄性小鼠比雌性小鼠更具适应性，并观察到AT基因敲除雌性小鼠的两个亚群。通过测量动脉血pH值，我们得出结论，AT对呼吸性酸中毒的代偿不是必需的，但对代谢性酸中毒的反应是必需的。
