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 #
5R01DK045788-16
Application #
8277342
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
2012-06-01
Budget End
2013-05-31
Support Year
16
Fiscal Year
2012
Total Cost
$286,076
Indirect Cost
$72,905
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; Verlander, Jill W (2014) Ammonia transport in the kidney by Rhesus glycoproteins. Am J Physiol Renal Physiol 306:F1107-20
Lee, Hyun-Wook; Verlander, Jill W; Handlogten, Mary E et al. (2014) Effect of collecting duct-specific deletion of both Rh B Glycoprotein (Rhbg) and Rh C Glycoprotein (Rhcg) on renal response to metabolic acidosis. Am J Physiol Renal Physiol 306:F389-400
Han, Ki-Hwan; Lee, Hyun-Wook; Handlogten, Mary E et al. (2013) Expression of the ammonia transporter family member, Rh B Glycoprotein, in the human kidney. Am J Physiol Renal Physiol 304:F972-81
Weiner, I David; Verlander, Jill W (2013) Renal ammonia metabolism and transport. Compr Physiol 3:201-20
Weiner, I David (2013) Endocrine and hypertensive disorders of potassium regulation: primary aldosteronism. Semin Nephrol 33:265-76
Weiner, I David; Verlander, Jill W (2011) Role of NH3 and NH4+ transporters in renal acid-base transport. Am J Physiol Renal Physiol 300:F11-23
Lee, Su-Youn; Shin, Jung-A; Kwon, H Moo et al. (2011) Renal ischemia-reperfusion injury causes intercalated cell-specific disruption of occludin in the collecting duct. Histochem Cell Biol 136:637-47
Han, Ki-Hwan; Lee, Hyun-Wook; Handlogten, Mary E et al. (2011) Effect of hypokalemia on renal expression of the ammonia transporter family members, Rh B Glycoprotein and Rh C Glycoprotein, in the rat kidney. Am J Physiol Renal Physiol 301:F823-32
Bishop, Jesse M; Verlander, Jill W; Lee, Hyun-Wook et al. (2010) Role of the Rhesus glycoprotein, Rh B glycoprotein, in renal ammonia excretion. Am J Physiol Renal Physiol 299:F1065-77
Weiner, I David; Verlander, Jill W (2010) Molecular physiology of the Rh ammonia transport proteins. Curr Opin Nephrol Hypertens 19:471-7

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