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.
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.
|Lee, Hyun-Wook; Osis, Gunars; Harris, Autumn N et al. (2018) NBCe1-A Regulates Proximal Tubule Ammonia Metabolism under Basal Conditions and in Response to Metabolic Acidosis. J Am Soc Nephrol 29:1182-1197|
|Harris, Autumn N; Grimm, P Richard; Lee, Hyun-Wook et al. (2018) Mechanism of Hyperkalemia-Induced Metabolic Acidosis. J Am Soc Nephrol 29:1411-1425|
|Harris, Autumn N; Lee, Hyun-Wook; Osis, Gunars et al. (2018) Differences in renal ammonia metabolism in male and female kidney. Am J Physiol Renal Physiol 315:F211-F222|
|Lee, Hyun-Wook; Osis, Gunars; Handlogten, Mary E et al. (2017) Proximal tubule glutamine synthetase expression is necessary for the normal response to dietary protein restriction. Am J Physiol Renal Physiol 313:F116-F125|
|Weiner, I David; Verlander, Jill W (2017) Ammonia Transporters and Their Role in Acid-Base Balance. Physiol Rev 97:465-494|
|Lee, Hyun-Wook; Handlogten, Mary E; Osis, Gunars et al. (2017) Expression of sodium-dependent dicarboxylate transporter 1 (NaDC1/SLC13A2) in normal and neoplastic human kidney. Am J Physiol Renal Physiol 312:F427-F435|
|Weiner, I David (2017) Roles of renal ammonia metabolism other than in acid-base homeostasis. Pediatr Nephrol 32:933-942|
|Canales, Benjamin K; Smith, Jennifer A; Weiner, I David et al. (2017) Polymorphisms in Renal Ammonia Metabolism Genes Correlate With 24-Hour Urine pH. Kidney Int Rep 2:1111-1121|
|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:|
|Lee, Hyun-Wook; Osis, Gunars; Handlogten, Mary E et al. (2016) Proximal tubule-specific glutamine synthetase deletion alters basal and acidosis-stimulated ammonia metabolism. Am J Physiol Renal Physiol 310:F1229-42|
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