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, published data and our preliminary data indicates that Rh glycoprotein B Glycoprotein (Rhbg) mediates a previously unrecognized role in renal ammonia metabolism. A second advance has been the recognition that Rhbg is expressed in principal cells, a cell not generally known to be involved in acid-base homeostasis, and that adaptive changes in principal cell Rhbg may be an important component of the renal response to metabolic acidosis. Thus, the overall aim of this application is to determine Rhbg's role in acid-base homeostasis and in potassium homeostasis. The first goal is to determine the specific role of Rhbg 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 Rhbg deletion. We will also generate mice with kidney-specific Rhbg and 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 Rhbg'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 Rhbg 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 Rhbg's role in the renal response to hypokalemia, and the specific contributions of intercalated cells and principal cells to Rhbg-mediated ion transport in response to hypokalemia.

Public Health Relevance

Acid-base disorders are common in veterans, and are associated with osteoporosis, muscle atrophy, growth retardation, renal stone disease and increased morbidity. They may also contribute to the progression of chronic kidney disease. The proposed studies will provide new insights into mechanisms of acid-base homeostasis, and thereby provide the necessary underpinnings for new and novel treatments for veterans with acid-base disorders.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000818-02
Application #
8198381
Study Section
Nephrology (NEPH)
Project Start
2011-07-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
Indirect Cost
Name
Veterans Health Administration
Department
Type
DUNS #
097378632
City
Gainesville
State
FL
Country
United States
Zip Code
32608
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:
Weiner, I David; Verlander, Jill W (2016) Recent advances in understanding renal ammonia metabolism and transport. Curr Opin Nephrol Hypertens 25:436-43
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; 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
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; 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:
Lee, Hyun-Wook; Verlander, Jill W; Bishop, Jesse M et al. (2013) Renal ammonia excretion in response to hypokalemia: effect of collecting duct-specific Rh C glycoprotein deletion. Am J Physiol Renal Physiol 304:F410-21

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