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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Proximal tubule NHE3 activity is inhibited by beta-arrestin-biased angiotensin II type 1 receptor signaling

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Author(s):
Carneiro de Morais, Carla P. [1] ; Polidoro, Juliano Z. [2] ; Ralph, Donna L. [3] ; Pessoa, Thaissa D. [2] ; Oliveira-Souza, Maria [2] ; Barauna, Valerio G. [4] ; Reboucas, Nancy A. [2] ; Malnic, Gerhard [2] ; McDonough, Alicia A. [3] ; Girardi, Adriana C. C. [1]
Total Authors: 10
Affiliation:
[1] Univ Sao Paulo, Sch Med, Heart Inst InCor, BR-05403900 Sao Paulo, SP - Brazil
[2] Univ Sao Paulo, Dept Phys & Biophys, BR-05403900 Sao Paulo, SP - Brazil
[3] Univ So Calif, Keck Sch Med, Dept Cell & Neurobiol, Los Angeles, CA 90033 - USA
[4] Univ Fed Espirito Santo, Dept Physiol Sci, Vitoria, Espirito Santo - Brazil
Total Affiliations: 4
Document type: Journal article
Source: AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY; v. 309, n. 8, p. C541-C550, OCT 15 2015.
Web of Science Citations: 4
Abstract

Physiological concentrations of angiotensin II (ANG II) upregulate the activity of Na+/H+ exchanger isoform 3 (NHE3) in the renal proximal tubule through activation of the ANG II type I (AT1) receptor/G protein-coupled signaling. This effect is key for maintenance of extracellular fluid volume homeostasis and blood pressure. Recent findings have shown that selective activation of the beta-arrestin-biased AT1 receptor signaling pathway induces diuresis and natriuresis independent of G protein-mediated signaling. This study tested the hypothesis that activation of this AT1 receptor/beta-arrestin signaling inhibits NHE3 activity in proximal tubule. To this end, we determined the effects of the compound TRV120023, which binds to the AT1R, blocks G-protein coupling, and stimulates beta-arrestin signaling on NHE3 function in vivo and in vitro. NHE3 activity was measured in both native proximal tubules, by stationary microperfusion, and in opossum proximal tubule (OKP) cells, by Na+-dependent intracellular pH recovery. We found that 10(-7) M TRV120023 remarkably inhibited proximal tubule NHE3 activity both in vivo and in vitro. Additionally, stimulation of NHE3 by ANG II was completely suppressed by TRV120023 both in vivo as well as in vitro. Inhibition of NHE3 activity by TRV120023 was associated with a decrease in NHE3 surface expression in OKP cells and with a redistribution from the body to the base of the microvilli in the rat proximal tubule. These findings indicate that biased signaling of the beta-arrestin pathway through the AT1 receptor inhibits NHE3 activity in the proximal tubule at least in part due to changes in NHE3 subcellular localization. (AU)

FAPESP's process: 12/10146-0 - Molecular mechanisms of regulation of the proximal tubular function in hypertension
Grantee:Adriana Castello Costa Girardi
Support type: Regular Research Grants
FAPESP's process: 13/50384-0 - Collaborative effort to determine the molecular bases of the blood pressure lowering effects of the incretin hormone GLP-1
Grantee:Adriana Castello Costa Girardi
Support type: Regular Research Grants
FAPESP's process: 13/10619-8 - Dipeptidyl peptidase IV as a potential target for the therapy of heart failure
Grantee:Adriana Castello Costa Girardi
Support type: Regular Research Grants