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Peptide Hormone Insulin Regulates Function, Expression, and SUMOylation of Organic Anion Transporter 3

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  • Theme: Celebrating Women in the Pharmaceutical Sciences
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Abstract

Organic anion transporter 3 (OAT3) plays an important role in the disposition of various anionic drugs which impacts the pharmacokinetics and pharmacodynamics of the therapeutics, thus influencing the pharmacological effects and toxicity of the drugs. In this study, we investigated the effect of insulin on the regulation of OAT3 function, expression, and SUMOylation. We demonstrated that insulin induced an increase in OAT3 transport activity through a dose- and time-dependent manner in COS-7 cells. The insulin-induced elevation in OAT3 function was blocked by PKA inhibitor H89, which correlated well with OAT3 protein expression. Moreover, both PKA activator Bt2-cAMP-induced increase and insulin-induced increase in OAT3 function were blocked by PKB inhibitor AKTi1/2. To further investigate the involvement of SUMOylation, we treated OAT3-expressing cells with insulin in presence or absence of H89 or AKTi1/2 followed by examining OAT3 SUMOylation. We showed that insulin enhanced OAT3 SUMOylation, and such enhancement was abrogated by H89 and AKTi1/2. Lastly, insulin increased OAT3 function and SUMOylation in rat kidney slice. In conclusion, our investigations demonstrated that insulin regulated OAT3 function, expression, and SUMOylation through PKA/PKB signaling pathway.

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Acknowledgments

This work was supported by grants (to Dr. Guofeng You) from National Institute of General Medical Sciences (R01-GM079123 and R01-GM097000).

We would like to thank Dr. Kexin Liu and his group from Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning Dalian Medical University for their technical help on kidney slice preparation.

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  1. Department of Pharmaceutics, Rutgers, the State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA

    Jinghui Zhang & Guofeng You

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  1. Jinghui Zhang
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Correspondence to Guofeng You.

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Zhang, J., You, G. Peptide Hormone Insulin Regulates Function, Expression, and SUMOylation of Organic Anion Transporter 3. AAPS J 23, 41 (2021). https://doi.org/10.1208/s12248-021-00575-z

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