The Defense against Whole‐Animal Respiratory Acidosis in AT 1A knockout mice

Numerous diseases cause acid‐base disturbances, and severe alterations in arterial pH (pH a ) can have devastating consequences for the patient. The renal proximal tubule (PT) normally handles ~80% of renal H⁺ secretion, and appropriately adjusts its rate of acid secretion ( J H ), most of which represents HCO 3 − reabsorption, in response to respiratory acidosis (RAc: increased [CO 2 ] → decreased pH) and metabolic acidosis(MAc: decreased [HCO 3 − ] → decreased pH). Rather than responding to changes in pH at the extracellular side of the basolateral (BL) membrane, the PT raises J H when [CO 2 ] BL rises or [HCO₃⁻] BL falls. How exactly the PT senses Δ[CO 2 ] BL and Δ[HCO 3 − ] BL and transduces the signal throughout the cellis poorly understood. However, our laboratory has made three observations. First, the knockout (KO) of receptor protein tyrosine phosphatase γ(RPTPγ), a novel extracellular CO 2 /HCO 3 − sensor localized in the PT BL membrane, eliminates the Δ J H produced by Δ[CO 2 ] BL or Δ[HCO 3 − ] BL , and substantially reduces the ability of the mouse to regulate pH a during MAc. Second, inhibitors of ErbB receptor tyrosine kinases at the BL membrane likewise eliminate the Δ J H response. And third, the Δ J H response requires active ACE to produce ANG II that, upon secretion, binds to apical AT 1A receptors. We hypothesize that RPTPγ and its downstream effectors (ErbB1, ErbB2, ACE, and AT 1A ) are also essential in the whole‐body responses to RAc. Here we describe a novel assay in which we subject WT vs AT 1A ⁻ / ⁻ mice to 8% inspired CO 2 to induce RAc. We cannulate the left carotid artery and, after recovery, sequentially sample arterial blood from conscious mice under control (Ctrl = ~0% CO 2 ) vs RAc conditions at 5 min, 1 h, 24 h, 48 h and 7 days post‐initiation to determine the ability of the mouse to defend pH a against the acid‐base disturbance. After 5 min of 8% CO 2 , in both WT and AT 1A ⁻ / ⁻ pH a decreases from ~7.41 to ~7.24, arterial p CO 2 increases from ~29 to ~64 mmHg, and [HCO 3 − ] a increases from ~18 to ~28 mM. 4 h post hypercapnia onset, pH a recovers to ~7.28 in both WT and AT 1A ‐/‐ mice, arterial pCO 2 increases to ~73 mmHg, and [HCO₃⁻] a increases to ~34 mM. At 48 h, pH a plateaus at ~7.34 (i.e. without returning to baseline values). These data indicate that the partial pH a recovery during RAc is similar in both WT and AT 1A ⁻ / ⁻ mice. Previous preliminary data showed that AT 1A ⁻ / ⁻ mice have a limited ability to defend pH a during MAc. However, AT 1A does not seem to be essential to defend pH a during RAc.