Differential effects of deleting the angiotensin receptor AT1A on the whole animal response to respiratory and metabolic acidosis in mice.

Abstract

During systemic acid-base disturbances, the respiratory system modulates CO₂ elimination, whereas the urinary system modulates H⁺ secretion-responses that tend to stabilize arterial pH (pH_a). Proximal tubules (PTs) are responsible for ∼80% of renal H⁺ secretion. Isolated PTs appear to sense and respond to acute changes in basolateral [CO₂] or [[Formula: see text]] using a mechanism that signals through apical angiotensin II AT_1A receptors. In the present study, we examine the whole animal responses to both respiratory acidosis (RAc: ↑[CO₂] → ↓pH_a) and metabolic acidosis (MAc: ↓[[Formula: see text]] → ↓pH_a) in wild-type (WT) versus AT_1A knockout (KO) mice. After catheterizing the carotid artery, we serially sample blood for arterial blood-gas analyses. We find that, in mice breathing 8% CO₂, pH_a 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_1A does not affect RAc compensation. During MAc (1% NH₄Cl in drinking water), WT males exhibit only a small/insignificant fall in pH_a, whereas WT females exhibit a larger/significant pH_a decrease. In another sexual dimorphism, AT_1A-KO males acidify on day 2 of MAc, but nearly recover by day 7, whereas KO females exhibit either of two responses: 1) adaptive, in which pH_a falls relatively little by day 2 and then recovers by day 7, and 2) maladaptive, in which pH_a falls at day 2 and remains depressed at day 7. Thus, AT_1A is crucial for defense against MAc in all but half the females, but not RAc.NEW & NOTEWORTHY 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_1A-KO females. From measurements of arterial pH, we conclude that AT_1A is not necessary for the compensation to RAc, but is necessary in the response to MAc.