SGK1/Nedd4 ‐2 signaling pathway regulates the activity of Human Organic Anion Transporters 3

Abstract Human organic anion transporter 3 (hOAT3) is localized at the basolateral membrane of renal proximal tubule cells and facilitates renal secretion of numerous clinical drugs, including anti‐HIV therapeutics, anti‐tumor drugs, antibiotics, antihypertension drugs, and anti‐inflammatories. In the present study, we explored the role of serum and glucocorticoid‐inducible kinase 1 (sgk1) in the regulation of hOAT3. We showed 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 substrate‐binding affinity Km. In contrast, treatment of cells with sgk‐specific inhibitor GSK650394 resulted in a dose‐dependent inhibition of hOAT3 transport activity. We further provided evidence that sgk1 regulation of hOAT3 activity was mediated by ubiquitin ligase Nedd4‐2, an enzyme previously shown to have inhibitory effect on hOAT3. We showed that sgk1 phosphorylated Nedd4‐2, weakened the association between Nedd4‐2 and hOAT3, and decreased hOAT3 ubiquitination. Functionally, sgk1‐stimulated hOAT3 transport activity was attenuated in the presence of a ligase‐dead mutant of Nedd4‐2. In summary, our investigation established for the first time that sgk1 stimulates hOAT3 transport activity by interfering with the inhibitory effect of Nedd4‐2 on the transporter.
Source: Biopharmaceutics and Drug Disposition - Category: Drugs & Pharmacology Authors: Tags: ORIGINAL PAPER Source Type: research