SGK1/Nedd4–2 signaling pathway regulates the activity of human organic anion transporters 3

Haoxun Wang, Guofeng You

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Human organic anion transporter 3 (hOAT3) is localized at the basolateral membrane of renal proximal tubule cells and facilitates the renal secretion of numerous clinical drugs, including anti-HIV therapeutics, anti-tumor drugs, antibiotics, antihypertension drugs and anti-inflammatories. The present study explored the role of serum and glucocorticoid-inducible kinase 1 (sgk1) in the regulation of hOAT3. It was shown that over-expression of sgk1 in hOAT3-expressing cells stimulated hOAT3 transport activity by enhancing the transporter expression at the plasma membrane, kinetically reflected as an increased maximal transport velocity Vmax without substantial change in the substrate-binding affinity Km. In contrast, treatment of cells with the sgk-specific inhibitor GSK650394 resulted in a dose-dependent inhibition of hOAT3 transport activity. Evidence was further provided that sgk1 regulation of hOAT3 activity was mediated by ubiquitin ligase Nedd4–2, an enzyme previously shown to have an inhibitory effect on hOAT3. It was shown that sgk1 phosphorylated Nedd4–2, weakened the association between Nedd4–2 and hOAT3, and decreased hOAT3 ubiquitination. Functionally, the sgk1-stimulated hOAT3 transport activity was attenuated in the presence of a ligase-dead mutant of Nedd4–2. In summary, the investigation established for the first time that sgk1 stimulates hOAT3 transport activity by interfering with the inhibitory effect of Nedd4–2 on the transporter.

Original languageEnglish (US)
Pages (from-to)449-457
Number of pages9
JournalBiopharmaceutics and Drug Disposition
Volume38
Issue number8
DOIs
StatePublished - Nov 2017

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science
  • Pharmacology (medical)

Keywords

  • drug transporter
  • organic anion transporter
  • regulation
  • serum and glucocorticoid-inducible kinase
  • ubiquitin ligase

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