IRBIT Mediates Trafficking and Activation of Na+,K+‐ATPase by Angiotensin II

Na+ reabsorption by the kidney is tightly regulated to maintain Na+, fluid and blood pressure homeostasis. Angiotensin II (Ang II) plays a critical role in Na+ reabsorption in the kidney during health and diseases conditions. Na+,K+-ATPase on the basolateral membrane is one of the important targets subjected to Ang II regulation. However, the mechanism by which Ang II activates Na+,K+-ATPase remains poorly understood. We have previously shown that IRBIT (inositol 1,4,5-triphosphate receptor binding protein released with inositol 1,4,5-triphosphate) binds and activates Na+/H+ exchanger (NHE3) in response to Ang II. By mass spectrometry analysis, we identified IRBIT as a novel binding protein of Na+,K+-ATPase, prompting us hypothesize that IRBIT might coordinate transcellular Na+ absorption by regulating apical NHE3 and basolateral Na+,K+-ATPase. Indeed, overexpression of IRBIT resulted in a greater activation of Na+,K+-ATPase activity by Ang II in OKP cells, whereas lentiviral shRNA-mediated knockdown of I...