Arginine vasopressin enhances pH_i regulation in the presence of HCO⁻₃ by stimulating three acid-base transport systems

Abstract

Growth factors raise intracellular pH (pH_i) by stimulating Na⁺/H⁺ exchange in the absence of HCO⁻₃ (refs 1-4). In mutant cells that lack the Na⁺/H⁺ exchange activity, this alkalinization does not occur, and the cells do not proliferate without artificial elevation of pH_i^5,6. It has therefore been widely suggested that an early pH_i increase is a necessary signal for mitogenesis. In the presence of HCO⁻₃ however, growth factors fail to raise pH_i in A431 cells⁷, renal mesangial cells⁸ and 3T3 fibroblasts⁹. In mesangial cells, arginine vasopressin (AVP) raises pH_i in the absence of HCO⁺₃, but lowers it when HCO⁻₃ is present; growth is stimulated under both conditions⁸. We report here that, in the presence of HCO⁻₃, AVP stimulates two potent HCO⁻₃ transporters, as well as the Na⁺/H⁺ exchanger. These are the Na⁺-depen-dent and Na⁺-independent Cl⁻/HCO⁻₃ exchangers. Our results indicate that AVP causes acidification in the presence of HCO⁻₃ because, at the resting pH_i, it stimulates Na⁺-independent Cl⁻/HCO⁻₃exchange (which lowers pH_i) more than it stimulates the sum of Na⁺/H⁺ exchange and Na⁺-dependent Cl⁻/HCO⁻₃ exchange (both of which raise pH_i). The stimulation of three acid-base transporters by the growth factor AVP greatly enhances the ability of the cell to regulate pH_i.