High sodium intake increases HCO^-₃ absorption in medullary thick ascending limb through adaptations in basolateral and apical Na⁺/H⁺ exchangers

A high sodium intake increases the capacity of the medullary thick ascending limb (MTAL) to absorb HCO^-₃. Here, we examined the role of the apical NHE3 and basolateral NHE1 Na⁺/H⁺ exchangers in this adaptation. MTALs from rats drinking H₂O or 0.28 M NaCl for 5-7 days were perfused in vitro. High sodium intake increased HCO^-₃ absorption rate by 60%. The increased HCO^-₃ absorptive capacity was mediated by an increase in apical NHE3 activity. Inhibiting basolateral NHE1 with bath amiloride eliminated 60% of the adaptive increase in HCO^-₃ absorption. Thus the majority of the increase in NHE3 activity was dependent on NHE1. A high sodium intake increased basolateral Na⁺/H⁺ exchange activity by 89% in association with an increase in NHE1 expression. High sodium intake increased apical Na+/H+ exchange activity by 30% under conditions in which basolateral Na⁺/H⁺ exchange was inhibited but did not change NHE3 abundance. These results suggest that high sodium intake increases HCO^-₃ absorptive capacity in the MTAL through 1) an adaptive increase in basolateral NHE1 activity that results secondarily in an increase in apical NHE3 activity; and 2) an adaptive increase in NHE3 activity, independent of NHE1 activity. These studies support a role for NHE1 in the long-term regulation of renal tubule function and suggest that the regulatory interaction whereby NHE1 enhances the activity of NHE3 in the MTAL plays a role in the chronic regulation of HCO^-₃ absorption. The adaptive increases in Na⁺/H⁺ exchange activity and HCO₃ absorption in the MTAL may play a role in enabling the kidneys to regulate acid-base balance during changes in sodium and volume balance.