The Na+/H+ exchanger is a ubiquitous transport system with a broad range of cellular functions. These functions depend upon the cell type and the location of the Na+/H+ exchanger within that cell. In the renal proximal tubule, the Na+/H+ exchanger is localized to the apical membrane where it participates in transepithelial Na+ absorption and H+ secretion. In vascular smooth muscle cells, Na+/H+ exchangers participate in pH regulation, vasoconstrictor-induced changes in cell pH, and volume regulation. Because of its many functions, the Na+/H+ exchanger is regulated in many ways. During the first funding period, we studied the Na+/H+ exchanger in renal brush border vesicles and in cultured vascular smooth muscle cells. In the next funding period, we plan to further characterize the mechanisms for regulation of the Na+/H+ exchanger in cultured proximal tubule epithelial cells and vascular smooth muscle cells, with emphasis on protein kinase C-dependent and -independent activation of the Na+/H+ exchanger by vasoactive agents, growth factors, acidosis, and hypokalemia. We hypothesize that activation of the Na+/H+ exchanger by angiotensin II in proximal tubule cells and vascular smooth muscle cells may occur by similar mechanisms or that other features of Na+/H+ exchange in epithelial and mesenchymal cells may be similar. Methods include measurement of cell pH and Ca2+ using fluorescent probes in cultured epithelial and vascular smooth muscle cells, inositol phosphate turnover, arachidonic acid release, and manipulation of G protein function with GTP analogues and specific inhibitors. Studies on the mechanisms of regulation of the Na+/H+ exchanger are important because this transport system is associated with numerous cellular functions like growth, differentiation, vasomotor tone, and cell volume regulation. In addition, alterations in Na+/H+ exchange are associated with pathological states, including hypertension, metabolic acidosis, renal insufficiency, and neoplasia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK034127-07
Application #
3232472
Study Section
General Medicine B Study Section (GMB)
Project Start
1984-07-01
Project End
1993-03-31
Budget Start
1991-04-01
Budget End
1992-03-31
Support Year
7
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Huang, C L; Takenawa, T; Ives, H E (1991) Platelet-derived growth factor-mediated Ca2+ entry is blocked by antibodies to phosphatidylinositol 4,5-bisphosphate but does not involve heparin-sensitive inositol 1,4,5-trisphosphate receptors. J Biol Chem 266:4045-8
Weiss, R H; Huang, C L; Ives, H E (1991) Sphingosine reverses growth inhibition caused by activation of protein kinase C in vascular smooth muscle cells. J Cell Physiol 149:307-12

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