A major advance in our understanding of acid-base homeostasis and ammonia metabolism is the identification that Rh glycoproteins are ammonia transporters. In the kidney, multiple lines of evidence suggest that Rh glycoprotein C Glycoprotein (Rhcg) is critically important in renal ammonia metabolism. A second advance has been the recognition that Rhcg is expressed in principal cells, a cell not generally known to be involved in acid-base homeostasis, and that principal cell Rhcg expression parallels ammonia excretion. Thus, principal cells may contribute to regulated transcellular ammonia secretion. Finally, Rhcg expression appears to be regulated through post-transcriptional mechanisms. The overall aim of this application is to determine Rhcg's role in acid-base homeostasis and in potassium homeostasis. The first goal is to determine the specific role of Rhcg in the renal response to metabolic acidosis. We will use Cre-loxP technology to generate transgenic mice with kidney-specific, intercalated cell-specific and principal cell-specific Rhcg deletion. We will then examine acid- base homeostasis in these mice under control conditions and in response to metabolic acidosis in order to determine the specific role of Rhcg in renal acid-base homeostasis, and the specific contributions of intercalated cells and principal cells to acid-base homeostasis.
Our second aim i s to determine Rhcg's specific role in the renal response to hypokalemia. We will again use Cre-loxP technology to generate transgenic mice with kidney- specific, intercalated cell-specific and principal cell-specific Rhcg deletion. We will then examine acid-base and potassium homeostasis in these mice under control conditions and in response to dietary potassium deficiency in order to determine the specific role of Rhcg in the renal response to hypokalemia, and the specific contributions of intercalated cells and principal cells to Rhcg-mediated ion transport in response to hypokalemia.

Public Health Relevance

Acid-base disorders are associated with renal stone disease, osteoporosis, muscle atrophy, growth retardation and increased morbidity. The proposed studies will provide new insights into the fundamental mechanisms of acid-base homeostasis, thereby providing underpinnings for new and novel treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK045788-17
Application #
8473206
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Ketchum, Christian J
Project Start
1993-08-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
17
Fiscal Year
2013
Total Cost
$276,063
Indirect Cost
$70,353
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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