Chronic regulation of the renal Na⁺/H⁺exchanger NHE3 by dopamine: translational and posttranslational mechanisms

Abstract

The intrarenal autocrine/paracrine dopamine (DA) system contributes to natriuresis in response to both acute and chronic Na+ loads. While the acute DA effect is well described, how DA induces natriuresis chronically is not known. We used an animal and a cell culture model to study the chronic effect of DA on a principal renal Na+ transporter, Na+/H+ exchanger-3 (NHE3). Intraperitoneal injection of Gludopa in rats for 2 days elevated DA excretion and decreased total renal cortical and apical brush-border NHE3 antigen. Chronic treatment of an opossum renal proximal cell line with DA decreased NHE3 activity, cell surface and total cellular NHE3 antigen, but not NHE3 transcript. The decrease in NHE3 antigen was dose and time dependent with maximal inhibition at 16–24 h and half maximal effect at 3 × 10−7 M. This is in contradistinction to the acute effect of DA on NHE3 (half maximal at 2 × 10−6 M), which was not associated with changes in total cellular NHE3 protein. The DA-induced decrease in total NHE3 protein was associated with decrease in NHE3 translation and mediated by cis-sequences in the NHE3 5′-untranslated region. DA also decreased cell surface and total cellular NHE3 protein half-life. The DA-induced decrease in total cellular NHE3 was partially blocked by proteasome inhibition but not by lysosome inhibition, and DA increased ubiquitylation of total and surface NHE3. In summary, chronic DA inhibits NHE3 with mechanisms distinct from its acute action and involves decreased NHE3 translation and increased NHE3 degradation, which are novel mechanisms for NHE3 regulation.

Dopamine D3 receptor inhibits the ubiquitin‐specific peptidase 48 to promote NHE3 degradation

“…We next determined whether D 3 R stimulation also regulates NHE3 expression in the long term. Although acute dopamine treatment was not associated with changes in total cellular NHE3 abundance, long‐term treatment with dopamine in opossum kidney cells reduced both total cellular and cell surface NHE3 expression (27). A 24‐h treatment with quinpirole (a mixed D 2 R/D 3 R agonist) decreased NHE3 protein expression in hRPTCs, an effect that was blocked by cotreatment with the specific D 3 R antagonist GR103691, indicating a D 3 R‐specific effect (Fig.…”

“…Protein ubiquitinylation is important for NHE3 internalization in yeast (26). Dopamine treatment increases cell surface NHE3 ubiquitinylation in opossum kidney cells (27).…”

Traditional and emerging roles for the SLC9 Na+/H+ exchangers

“…Recently significant insights into how the NHERFs and ezrin affect NHE3 activity, the mechanisms underlying angiotensin II mediated activation of the exchanger, the role of SGK signalling and NHE3 lipid interactions on activity have been made [1,149,30,8,9,184,112,68,117,64].…”

Gut microbiota in hypertension

“…An important counter-regulatory natriuretic pathway is afforded by the renal dopaminergic system. Aberrations of this system are involved in the pathogenesis of hypertension (26, 31–35), including that associated with obesity (36–38). However, the gastrointestinal tract has to be integrated in the overall regulation sodium balance and blood pressure because it the first organ exposed to ingested sodium (39, 40).…”