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Molecular and Cellular Biology, January 2005, p. 575-589, Vol. 25, No. 2
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.2.575-589.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Phosphatidylinositol 3-Kinase-Mediated Effects of Glucose on Vacuolar H+-ATPase Assembly, Translocation, and Acidification of Intracellular Compartments in Renal Epithelial Cells{dagger}

Yuri Y. Sautin,1* Ming Lu,2 Andrew Gaugler,1 Li Zhang,1 and Stephen L. Gluck2

Department of Medicine, University of Florida College of Medicine, Gainesville, Florida,1 Department of Medicine, University of California, San Francisco, San Francisco, California2

Received 22 March 2004/ Returned for modification 25 June 2004/ Accepted 20 October 2004

Vacuolar H+-ATPases (V-ATPases) are a family of ATP-driven proton pumps. They maintain pH gradients between intracellular compartments and are required for proton secretion out of the cytoplasm. Mechanisms of extrinsic control of V-ATPase are poorly understood. Previous studies showed that glucose is an important regulator of V-ATPase assembly in Saccharomyces cerevisiae. Human V-ATPase directly interacts with aldolase, providing a coupling mechanism for glucose metabolism and V-ATPase function. Here we show that glucose is a crucial regulator of V-ATPase in renal epithelial cells and that the effect of glucose is mediated by phosphatidylinositol 3-kinase (PI3K). Glucose stimulates V-ATPase-dependent acidification of the intracellular compartments in human proximal tubular cells HK-2 and porcine renal epithelial cells LLC-PK1. Glucose induces rapid ATP-independent assembly of the V1 and Vo domains of V-ATPase and extensive translocation of the V-ATPase V1 and Vo domains between different membrane pools and between membranes and the cytoplasm. In HK-2 cells, glucose stimulates polarized translocation of V-ATPase to the apical plasma membrane. The effects of glucose on V-ATPase trafficking and assembly can be abolished by pretreatment with the PI3K inhibitor LY294002 and can be reproduced in glucose-deprived cells by adenoviral expression of the constitutively active catalytic subunit p110{alpha} of PI3K. Taken together these data provide evidence that, in renal epithelial cells, glucose plays an important role in the control of V-ATPase-dependent acidification of intracellular compartments and V-ATPase assembly and trafficking and that the effects of glucose are mediated by PI3K-dependent signaling.

* Corresponding author. Mailing address: Department of Medicine, Division of Nephrology, Box 100224, University of Florida, 1600 SW Archer Rd., Gainesville, FL 32610-0224. Phone: (352) 392-2448. Fax: (352) 392-5465. E-mail: sautiyy{at}medicine.ufl.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, January 2005, p. 575-589, Vol. 25, No. 2
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.2.575-589.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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