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Mitogen-Stimulated and Rapamycin-Sensitive Glucose Transporter 12 Targeting and Functional Glucose Transport in Renal Epithelial Cells

The University of Melbourne, Department of Medicine (A.L.W.-O., C.L.D., S.R.), St. Vincent’s Hospital, Melbourne, Fitzroy, Victoria 3065, Australia; and The University of Melbourne, Department of Genetics (A.L.W.-O.), Parkville, Victoria 3052, Australia

Address all correspondence and requests for reprints to: Dr. Suzanne Rogers, The University of Melbourne, Department of Medicine, St. Vincent’s Hospital, Melbourne, Fitzroy, Victoria 3065, Australia. E-mail: s.rogers{at}medicine.unimelb.edu.au.

We hypothesized that glucose transporter 12 (GLUT12) is involved in regulation of glucose flux in distal renal tubules in response to elevated glucose. We used the Madin-Darby canine kidney polarized epithelial cell model and neutralizing antibodies to analyze GLUT12 targeting and directional GLUT12-mediated glucose transport. At physiological glucose concentrations, GLUT12 was localized to a perinuclear position. High glucose and serum treatment resulted in GLUT12 localization to the apical membrane. This mitogen-stimulated targeting of GLUT12 was inhibited by rapamycin, the specific inhibitor of mammalian target of rapamycin (mTOR). The functional role of GLUT12 was also examined. We constructed a GLUT12 cDNA containing a c-Myc epitope tag in the fifth exofacial loop. Assays of glucose transport at the apical membrane were performed using Transwell filters. By comparing transport assays in the presence of neutralizing anti-c-Myc monoclonal antibody, we specifically measured GLUT12-mediated glucose transport at the apical surface. GLUT12-mediated glucose transport was mitogen dependent and rapamycin sensitive. Our results implicate mTOR signaling in a novel pathway of glucose transporter protein targeting and glucose transport. Activity of the mTOR pathway has been associated with diabetic kidney disease. Our results provide evidence for a link between GLUT12 protein trafficking, glucose transport and signaling molecules central to the control of metabolic disease processes.

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