Kidney Blood Press Res 2014 Jan 01;396:591-9. doi: 10.1159/000368469.

Downregulation of peptide transporters PEPT1 and PEPT2 by oxidative stress responsive kinase OSR1.

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BACKGROUND/AIMS: OSR1 (oxidative-stress-responsive kinase 1) participates in the regulation of renal tubular ion transport, cell volume and blood pressure. Whether OSR1 contributes to the regulation of organic solute transport remained; however, elusive. The present study thus explored the OSR1 sensitivity of the peptide transporters PEPT1 and PEPT2. METHODS: cRNA encoding PEPT1 or PEPT2 were injected into Xenopus oocytes without or with additional injection of cRNA encoding wild-type OSR1, WNK1 insensitive inactive (T185A)OSR1, constitutively active (T185E)OSR1, and catalytically inactive (D164A)OSR1. Electrogenic peptide (glycine-glycine) transport was determined by dual electrode voltage clamp, the abundance of hemagglutinin-tagged PEPT2 (PEPT2-HA) by chemiluminescence. RESULTS: In Xenopus oocytes injected with cRNA encoding PEPT1 or PEPT2, but not in oocytes injected with water, the dipeptide gly-gly (2 mM) generated an appreciable inward current (I(gly-gly)). Coexpression of OSR1 significantly decreased Igly-gly in both PEPT1 and PEPT2 expressing oocytes. The effect of OSR1 coexpression on Igly-gly in PEPT1 expressing oocytes was mimicked by coexpression of (T185E)OSR1, but not of (D164A)OSR1 or (T185A)OSR1. Kinetic analysis revealed that coexpression of OSR1 decreased maximal Igly-gly. OSR1 further decreased the PEPT2-HA protein abundance in the cell membrane. CONCLUSION: OSR1 has the capacity to downregulate the peptide transporters PEPT1 and PEPT2 by decreasing the carrier protein abundance in the cell membrane.

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Species referenced: Xenopus
Genes referenced: osr1 slc15a1 slc15a2 wnk1