A major advance in our understanding of key renal function is the recent recognition that the enzyme glutamine synthetase may mediate critical roles in renal electrolyte and nitrogen metabolism. Glutamine synthetase mediates the conversion of NH4+ and glutamate into glutamine, thereby "ungenerating" ammonia and "regenerating" the useful amino acid glutamine. Glutamine synthetase is expressed in multiple distinct cell types in the kidney, including cells involved in ammonia generation (proximal tubule) and those traditionally thought to be involved solely in ammonia transport (intercalated cells). The presence of glutamine synthetase in these cell types, and our preliminary data identifying its regulation in multiple conditions suggests novel and new mechanisms regulating renal ammonia metabolism and in the regulation of nitrogen balance. The overall aim of this application is to determine the roles of glutamine synthetase in the different major cell types in the kidney in which it is expressed in renal ammonia, acid-base, potassium and nitrogen metabolism. The first goal is to determine the specific role of glutamine synthetase expression in the proximal tubule. We will use Cre-loxP technology to generate mice with proximal tubule-specific glutamine synthetase deletion, which we will use to determine the role of proximal tubule glutamine synthetase in normal acid-base homeostasis, and in the renal response to metabolic acidosis, hypokalemia and dietary protein restriction.
Our second aim i s to determine the specific role of glutamine synthetase expression in intercalated cells. We will use Cre-loxP technology to generate mice with intercalated cell-specific glutamine synthetase deletion. We will use these mice to determine the role of intercalated cell glutamine synthetase in normal acid- base homeostasis, and in the renal response to metabolic acidosis, hypokalemia and dietary protein restriction.

Public Health Relevance

A major function for the kidneys is to maintain appropriate levels of acid, naturally-generated antacid, potassium and electrolytes in the blood which are necessary for normal health. The studies in this project will significantly advance our understanding of the mechanisms through which the kidney does this by determining the role of a key protein, glutamine synthetase, in the kidney's response to non-stressed conditions, in response to acid loads, in response to deficiency of the key mineral, potassium, and in response to dietary protein restriction. The findings obtained will substantially advance our understanding of how the kidneys maintain normal health under a wide variety of conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK045788-18
Application #
8736102
Study Section
Special Emphasis Panel (ZRG1-DKUS-P (80))
Program Officer
Ketchum, Christian J
Project Start
1993-08-01
Project End
2018-03-31
Budget Start
2014-06-19
Budget End
2015-03-31
Support Year
18
Fiscal Year
2014
Total Cost
$294,930
Indirect Cost
$77,430
Name
University of Florida
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Weiner, I David (2016) Roles of renal ammonia metabolism other than in acid-base homeostasis. Pediatr Nephrol :
Osis, Gunars; Handlogten, Mary E; Lee, Hyun-Wook et al. (2016) Effect of NBCe1 deletion on renal citrate and 2-oxoglutarate handling. Physiol Rep 4:
Weiner, I David (2016) New insights into the molecular regulation of urine concentration. Am J Physiol Renal Physiol 311:F184-5
Lee, Su-Youn; Lee, Sae-Jin; Piao, Hong-Lin et al. (2016) Hydration status affects osteopontin expression in the rat kidney. J Vet Sci 17:269-77
Weiner, I David (2016) Untangling the complex relationship between dietary acid load and glucocorticoid metabolism. Kidney Int 90:247-9
Weiner, I David; Verlander, Jill W (2016) Recent advances in understanding renal ammonia metabolism and transport. Curr Opin Nephrol Hypertens 25:436-43
Lee, Hyun-Wook; Osis, Gunars; Handlogten, Mary E et al. (2015) Effect of dietary protein restriction on renal ammonia metabolism. Am J Physiol Renal Physiol 308:F1463-73
Handlogten, Mary E; Osis, Gunars; Lee, Hyun-Wook et al. (2015) NBCe1 expression is required for normal renal ammonia metabolism. Am J Physiol Renal Physiol 309:F658-66
Weiner, I David; Mitch, William E; Sands, Jeff M (2015) Urea and Ammonia Metabolism and the Control of Renal Nitrogen Excretion. Clin J Am Soc Nephrol 10:1444-58
Weiner, I David; Leader, John P; Bedford, Jennifer J et al. (2014) Effects of chronic lithium administration on renal acid excretion in humans and rats. Physiol Rep 2:

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