Role of the AT 1A receptor in the HCO 3 ‐induced inhibition of HCO 3 reabsorption by mouse proximal tubules

Previous works showed that the proximal tubule (PT) senses the changes of basolateral (BL) [CO 2 ] on HCO 3 reabsorption ( J HCO 3 ) requires an active apical AT 1 receptor. I hypothesized that an active apical AT 1 receptor is critical for the PT HCO 3 sensitivity. In isolated perfused wild type (WT) mouse PT, I increased [HCO 3 ] BL from 0, 22 to 44 mM (fixed [CO 2 ] BL = 5%, pH BL = 7.4), caused the J HCO 3 fall from 235 ± 13 (n = 6), 144 ± 7 (baseline, n = 30) to 58 ± 13 pmol mm −1 min −1 (n = 6, p < 0.01). Luminal 10 −8 M candesartan (AT 1 inhibitor) reduced the baseline J HCO 3 by ~51% (71 ± 8, n = 12, p < 0.01), and the PT response on J HCO 3 to 0 mM [HCO 3 ] BL (90 ± 9, n = 6) or 44 mM [HCO 3 ] BL (70 ± 12, n = 6) was eliminated. Whereas, luminal 10 −7 M PD123319 (AT 2 inhibitor) did not affect the PT HCO 3 sensitivity. Added BL 240 nM lisinopril (ACE inhibitor) to block the endogenous ANG II generation and thereby secretion to the PT lumen, the data was identical to the candesartan data above. Finally, isolated perfused the AT 1A ‐null mouse PT, the baseline J HCO 3 fell by ~23% (110 ± 9, n = 12, p = 0.01), the PT response to 0 mM [HCO 3 ] BL (113 ± 11, n = 6) was eliminated, and the J HCO 3 fell to pedestal in response of 44 mM [HCO 3 ] BL (48 ± 9, n = 6, p = 0.82). Thus, the work is consistent with the idea that the PT HCO 3 sensitivity on J HCO 3 requires an active apical AT 1 receptor. High [HCO 3 ] BL is a more powerful modulator ruling out the PT adaptation mechanism during the AT 1A signal‐transduction cascade is frozen.