Zhou Y, Bouyer P, Boron WF. Role of the AT1A receptor in the CO 2-induced stimulation of HCO 3 Ϫ reabsorption by renal proximal tubules. Am J Physiol Renal Physiol 293: F110-F120, 2007. First published March 13, 2007; doi:10.1152/ajprenal.00516.2006.-The proximal tubule (PT) is major site for the reabsorption of filtered HCO 3 Ϫ . Previous work on the rabbit PT showed that 1) increases in basolateral (BL) CO 2 concentration ([CO2]BL) raise the HCO 3 Ϫ reabsorption rate (J HCO 3 ), and 2) the increase that luminal angiotensin II (ANG II) produces in J HCO 3 is greatest at 0% [CO2]BL and falls to nearly zero at 20%. Here, we investigate the role of angiotensin receptors in the [CO2]BL dependence of JHCO 3 in isolated perfused PTs. We found that, in rabbit S2 PT segments, luminal 10 Ϫ8 M saralasin (peptide antagonist of ANG II receptors), lowers baseline JHCO 3 (5% CO2) to the value normally seen at 0% in the absence of inhibitors and eliminates the JHCO 3 response to changes in [CO2]BL. However, basolateral 10 Ϫ8 M saralasin has no effect. As with saralasin, luminal 10 Ϫ8 M candesartan (AT1 antagonist) reduces baseline JHCO 3 and eliminates the [CO2]BL dependence of JHCO 3 . Luminal 10 Ϫ7 M PD 123319 (AT2 antagonist) has no effect. Finally, we compared PTs from wild-type and AT1A-null mice of the same genetic background. Knocking out AT1A modestly lowers baseline JHCO 3 and, like luminal saralasin or candesartan in rabbits, eliminates the JHCO 3 response to changes in [CO2]BL. Our accumulated evidence suggests that ANG II endogenous to the PT binds to the apical AT1A receptor and that this interaction is critical for both baseline JHCO 3 and its response to changes in [CO2]BL. Neither apical AT2 receptors nor basolateral ANG II receptors are involved in these processes. kidney; angiotensin; acid-base; out-of-equilibrium CO 2/HCO3 Ϫ solutions; fluid reabsorption THE KIDNEY PLAYS A KEY ROLE in regulating the volume and acid-base balance of the extracellular fluid. For example, in response to acute respiratory acidosis (i.e., a rise in PCO 2 that causes a fall in pH), the kidney rapidly stimulates H ϩ secretion, as shown in the 1950s by Relman et al. (62), Brazeau and Gilman (10), and Dorman et al. (21). The response occurs even in the denervated kidney (81). Moreover, acute respiratory alkalosis inhibits H ϩ secretion (45). Part of the response to respiratory acidosis is mediated by the renal proximal tubule (PT), which reabsorbs a near-isosmotic fluid that represents about two-thirds of the fluid and ϳ80% of the HCO 3 Ϫ filtered by the glomerulus. The PT cell actively secretes H ϩ into the tubule lumen (2, 7, 71) and uses this H ϩ to titrate filtered HCO 3 Ϫ in the lumen to CO 2 and H 2 O, catalyzed by apical carbonic anhydrase IV (11,72,74 Ϫ ] (90). In addition to acid-base disturbances, another powerful modulator of PT acid-base transport is angiotensin II (ANG II). Many investigators have shown that ANG II, added to the apical or basolateral solution, has a biphasic concentration-dependent effect on the rates of...