Adenosine A2A receptor blocks the A 1 receptor inhibition of renal Na + transport and oxygen consumption.

A high renal oxygen (O2 ) need is primarily associated with the renal tubular O2 consumption (VO2 ) necessary for a high rate of sodium (Na+ ) transport. Limited O2 availability leads to increased levels of adenosine, which regulates the kidney via activation of both A1 and A2A adenosine receptors (A1R and A2AR, respectively). The relative contributions of A1R and A2AR to the regulation of renal Na+ transport and VO2 have not been determined. We demonstrated that A1R activation has a dose-dependent biphasic effect on both renal Na+ /H+ exchanger-3 (NHE3), a major player in Na+ transport, and VO2 . Here, we report concentration-dependent effects of adenosine: less than 5 × 10-7  M adenosine-stimulated NHE3 activity; between 5 × 10-7  M and 10-5  M adenosine-inhibited NHE3 activity; and greater than 10-5  M adenosine reversed the change in NHE3 activity (returned to baseline). A1R activation mediated the activation and inhibition of NHE3 activity, whereas 10-4  M adenosine had no effect on the NHE3 activity due to A2AR activation. The following occurred when A1R and A2AR were activated: (a) Blockade of the A2AR receptor restored the NHE3 inhibition mediated by A1R activation, (b) the NHE-dependent effect on VO2 mediated by A1R activation became NHE independent, and (c) A2AR bound to A1R. In summary, A1R affects VO2 via NHE-dependent mechanisms, whereas A2AR acts via NHE-independent mechanisms. When both A1R and A2AR are activated, the A2AR effect on NHE3 and VO2 predominates, possibly via an A1R-A2AR protein interaction. A2AR-A1R heterodimerization is proposed as the molecular mechanism enabling the NHE-independent control of renal VO2 .