The regulation of human organic anion transporter 4 by insulin-like growth factor 1 and protein kinase B signaling

Human organic anion transporter 4 (hOAT4), mainly expressed in the kidney and placenta, is essential for the disposition of numerous drugs, toxins, and endogenous substances. Insulin-like growth factor 1 (IGF-1) is a hormone generated in the liver and plays important roles in systemic growth, development, and metabolism. In the current study, we explored the regulatory effects of IGF-1 and downstream signaling on the transport activity, protein expression, and SUMOylation of hOAT4. We showed that IGF-1 significantly increased the transport activity, expression, and maximal transport velocity V_max of hOAT4 in kidney-derived cells. This stimulatory effect of IGF-1 on hOAT4 activity was also confirmed in cells derived from the human placenta. The increased activity and expression were correlated well with the reduced degradation rate of hOAT4 at the cell surface. Furthermore, IGF-1 significantly increased hOAT4 SUMOylation, and protein kinase B (PKB)-specific inhibitors blocked the IGF-1-induced regulations on hOAT4. In conclusion, our study demonstrates that the hepatic hormone IGF-1 regulates hOAT4 expressed in the kidney and placenta through the PKB signaling pathway. Our results support the remote sensing and signaling theory, where OATs play a central role in the remote communications among distal tissues.