Effects of acid challenges on type 2 angiotensin II receptor-sensitive ammonia production by the proximal tubule

Angiotensin II (ANG II) acting through its type 1 (AT(1)) receptor stimulates total ammonia (tNH(3)) production by the proximal tubule. The present studies explored the role of ANG II type 2 (AT(2)) receptors in modulating the stimulatory effects of ANG II on tNH(3) production. Mouse S2 proximal tubule segments derived from 18-h and 7-day acid-loaded mice, and non-acid-loaded controls were dissected and microperfused in vitro. Adding ANG II to the luminal perfusion solution resulted in different increments in tNH(3) production rates in tubules derived from 18-h vs. 7-day acid-loaded mice such that the increase in tNH(3) production with ANG II was higher in tubules derived from 18-h acid-loaded mice compared with those derived from control and 7-day acid-loaded mice. Adding the AT(2) receptor blocker PD123319 with ANG II increased ANG II-stimulated tNH3 production in S2 segments from control and 7-day acid-loaded mice but not in those from 18-h acid-loaded mice, and this increased effect of PD123319 was associated with higher AT(2) receptor protein levels in brush-border membranes. Studies in cultured proximal tubule cells demonstrated that 2-h exposure to pH 7.0 reduced the modulating effect of PD123319 on ANG II-simulated tNH(3) production and reduced cell surface AT2 receptor levels. We concluded that AT(2) receptors reduce the stimulatory effect of ANG II on proximal tubule tNH(3) production and that the time-dependent impact of AT(2) receptor blockade on the ANG II-stimulated tNH(3) production corresponded to time-dependent changes in AT(2) receptor cell surface expression in the proximal tubule.