title: 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.
authors: Dept. of Internal Medicine, Univ. of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8885, USA.
authors: Ming Chang
authors: MC
authors: Hu
authors: Francesca
authors: F
authors: Di Sole
authors: Jianning
authors: J
authors: Zhang
authors: Paul
authors: P
authors: McLeroy
authors: Orson W
authors: OW
authors: Moe
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology*; D015259:Dopamine Agents / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006207:Half-Life; D066298:In Vitro Techniques; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D023421:Models, Animal; D009893:Opossums; D014176:Protein Biosynthesis / Q000187:drug effects*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics* / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D015259:Dopamine Agents; C000613387:Slc9a3 protein, rat; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; C017342:gamma-glutamyl DOPA; D004295:Dihydroxyphenylalanine; D004298:Dopamine
keywords: 5′-untranslated region; NHE3; dopamine; natriuresis; ubiquitylation