Rapid activation of Na+/H+-exchange in MDCK cells by aldosterone involves MAP-kinases ERK 1/2

The mineralocorticoid aldosterone is essential for the adequate regulation of electrolyte homeostasis, extracellular volume and blood pressure. As a s teroid hormone it influences cellular functions by genomic actions. Previou sly it has been shown that aldosterone can activate Na+/H+-exchange (NHE) b y a rapid, nongenomic mechanism. Because (1) NHE can be regulated by ERK1/2 (extracellular signal-regulated kinase) and (2) steroids have been reporte d to rapidly activate ERK1/2, we tested the hypothesis that activation of N HE by aldosterone involves ERK1/2, using MDCK-C11 cells. We show that nanom olar concentrations of aldosterone induce a rapid, non-genomic activation o f NHE, which is characterized by an increased affinity for H+ with minor ch anges in the maximum transport rate. Accordingly, aldosterone led to an inc rease of cytosolic steady-state pH. The aldosterone-induced activation of N HE was prevented by the two specific inhibitors of ERK1/2 activation, PD 98 059 (2.5 . 10(-5) mol/l) and U0126 (10(-5) mol/l). Furthermore, in the pres ence of U0126 there was no aldosterone-induced increase of steady-state pH. Finally, aldosterone induced a rapid phosphorylation of ERK1/2, indicating its ability to activate ERK1/2. The data presented here support the hypoth esis that the rapid activation of NHE by aldosterone at nanomolar concentra tions involves ERK1/2. Thus, in certain cell types, the MARK cascade may re present an additional pathway mediating rapid aldosterone effects.