A primary function of the kidneys is to maintain acid-base homeostasis. This involves dual roles of the kidneys, filtered bicarbonate reabsorption and new bicarbonate generation through the process of net acid excretion. The proximal tubule reabsorbs approximately 80% of filtered bicarbonate, and the basolateral membrane protein, Na-bicarbonate cotransporter, electrogenic, isoform 1 (NBCE1), is critical in this process. The proximal tubule also has a major role in new bicarbonate generation and net acid excretion because it is the primary site of renal ammonia production. Ammonia production and excretion is quantitatively the major mechanism of net acid excretion and accounts for almost all of the response to acid-base disturbances. We recently identified that NBCE1 may have a previously unrecognized central role in the regulation of proximal tubule ammonia production. People with familial proximal renal tubular acidosis, a genetic disease almost always due to mutations in NBCE1, have abnormal basal and acidosis-stimulated ammonia excretion. We have identified that mice with NBCE1 deletion also have abnormal ammonia excretion, and that there are specific abnormalities in the expression of each of the major proteins involved in proximal tubule ammonia production and transport in these mice. The overall aim of this application is to determine the mechanism through which NBCE1 regulates proximal tubule ammonia metabolism and to determine its role in the renal response to metabolic acidosis and hypokalemia. We will use a variety of experimental approaches, including whole animal physiology, perfused tubule studies with measurement of intracellular pH and examination of cultured proximal renal tubule cells. The net result of these studies will be to substantially advance our understanding of acid-base homeostasis by identifying and understanding a critical mechanism in the regulation of proximal tubule ammonia metabolism, and thereby in acid-base homeostasis.

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, NBCe1, in the regulation of the major mechanism through the kidneys excrete acid through the generation and excretion of ammonia. The studies in this project will determine the role of NBCe1 in the kidney's production of ammonia under non-stressed conditions, in response to acid loads, in response to deficiency of the key mineral, potassium, and in response to dietary protein restriction. These studies will also determine the mechanism through which NBCe1 regulates renal ammonia metabolism. 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 #
1R01DK107798-01
Application #
9008851
Study Section
Special Emphasis Panel (KMBD)
Program Officer
Ketchum, Christian J
Project Start
2015-12-15
Project End
2019-11-30
Budget Start
2015-12-15
Budget End
2016-11-30
Support Year
1
Fiscal Year
2016
Total Cost
$305,100
Indirect Cost
$80,100
Name
University of Florida
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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
Fang, Lijuan; Lee, Hyun-Wook; Chen, Chao et al. (2018) Expression of the B splice variant of NBCe1 (SLC4A4) in the mouse kidney. Am J Physiol Renal Physiol 315:F417-F428
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
Chen, Lihe; Lee, Jae Wook; Chou, Chung-Lin et al. (2017) Transcriptomes of major renal collecting duct cell types in mouse identified by single-cell RNA-seq. Proc Natl Acad Sci U S A 114:E9989-E9998
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

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