Background/Aims: The Na<sup>+</sup>-coupled phosphate transporter NaPi-IIa is the main carrier accomplishing renal tubular phosphate reabsorption. It is driven by the electrochemical Na<sup>+</sup> gradient across the apical cell membrane, which is maintained by Na<sup>+</sup> extrusion across the basolateral cell membrane through the Na<sup>+</sup>/K<sup>+</sup> ATPase. The operation of NaPi-IIa thus requires energy in order to avoid cellular Na<sup>+</sup> accumulation and K<sup>+</sup> loss with eventual decrease of cell membrane potential, Cl<sup>-</sup> entry and cell swelling. Upon energy depletion, early inhibition of Na<sup>+</sup>-coupled transport processes may delay cell swelling and thus foster cell survival. Energy depletion is sensed by the AMP-activated protein kinase (AMPK), a serine/threonine kinase stimulating several cellular mechanisms increasing energy production and limiting energy utilization. The present study explored whether AMPK influences the activity of NAPi-IIa. Methods: cRNA encoding NAPi-IIa was injected into Xenopus oocytes with or without additional expression of wild-type AMPK (AMPK<sup>α1</sup>-HA+AMPK<sup>β1</sup>-Flag+AMPK<sup>γ1</sup>-HA), of inactive AMPK<sup>αK45R</sup> (AMPK<sup>α1K45R</sup>+AMPK<sup>β1</sup>-Flag+AMPK<sup>γ1</sup>-HA) or of constitutively active AMPK<sup>γR70Q</sup> (AMPK<sup>α1</sup>-HA+AMPK<sup>β1</sup>-Flag+AMPKγ1<sup>R70Q</sup>). NaPi-IIa activity was estimated from phosphate-induced current in dual electrode voltage clamp experiments. Results: In NaPi-IIa-expressing, but not in water-injected Xenopus oocytes, the addition of phosphate (1 mM) to the extracellular bath solution generated a current (I<sub>p</sub>), which was significantly decreased by coexpression of wild-type AMPK and of AMPK<sup>γR70Q</sup> but not of AMPK<sup>αK45R</sup>. The phosphate-induced current in NaPi-IIa- and AMPK-expressing Xenopus ooocytes was significantly increased by AMPK inhibitor Compound C (20 µM). Kinetic analysis revealed that AMPK significantly decreased the maximal transport rate. Conclusion: The AMP-activated protein kinase AMPK is a powerful regulator of NaPi-IIa and thus of renal tubular phosphate transport.