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Abstract: SA-PO1049

Signaling through the Angiotensin-II Type 2 Receptor (AT2R) Suppresses AT1R-Induced SGK1 Phosphorylation and NHE3 Activity

Session Information

  • Na+, K+, Cl-
    November 04, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Fluid, Electrolytes, and Acid-Base

  • 703 Na+, K+, Cl- Basic


  • Suri, Vikram, University of California- San Francisco, San Francisco, California, United States
  • Pearce, David, University of California San Francisco, San Francisco, California, United States

Activation of the Angiotensin Type 1 Receptor (AT1R) by Angiotensin-II has been shown to enhance proximal tubular sodium reabsorption via induction of NHE3, as well as distal sodium reabsorption via ENAC. Evidence from the literature supports a role for SGK1 as a critical signaling intermediate in the activation of both transporter systems. The Angiotensin Type 2 Receptor (AT2R) is a well-described receptor that has been shown to exert beneficial effects on blood pressure and natriuresis, and these effects are hypothesized to occur through antagonism of AT1R. In this study, we hypothesized that AT2R suppresses Angiotensin-II-mediated induction of SGK1 activation by AT1R.


HEK293 cells were transfected with constructs expressing AT1R, AT2R, or both, and stimulated with Angiotensin-II. In order to correlate suppression of SGK1 phosphorylation with transporter activity, we measured the Na-dependent recovery from an acid load, as a marker of NHE3 activity (using Bafilomycin A1 and 1uM EIPA to inhibit the v-H+-ATPase and NHE1, respectively). MDCK-2 cells were transfected with constructs expressing AT1R, AT2R, or both, loaded with the pH-sensitive dye BCECF-AM, stimulated with Angiotensin-II, and subjected to an acute acid load. Cytosolic pH was measured using ratiometric fluorescence measurements and calibration with Nigericin clamp.


In these experiments, AT2R consistently suppressed AT1R-mediated SGK1 phosphorylation (at S422) by approximately 50% at 30 minutes (as measured by immunoblot). In addition, our data suggests that this suppression may occur through delayed kinetics of SGK1 phosphorylation. In response to an acute acid load, MDCK-2 cells that co-express AT1R and AT2R showed diminished/delayed recovery from an acid load (dpHi/dt), as compared to cells that express either AT1R or AT2R alone.


We conclude from these data that co-expression and activation of AT2R suppresses AT1R-mediated SGK1 phosphorylation and downstream NHE3 activation, and these effects may underlie the observed natriuretic effect of AT2R agonists.


  • Other NIH Support