The mammalian renal pelvis is a pouch-like structure into which urine flows from the terminal portions of the collecting ducts. There is increasing evidence that the uroepithelial cells lining the renal pelvis do not simply perform a barrier function in protecting the underlying tissue from large changes in urinary pH and ion concentration but may play an important role in whole body sodium and water balance, and blood pressure control. In this regard, previous studies have demonstrated that the renal pelvic uroepithelium mediates a renorenal reflex response wherein changes in renal pelvic hydrostatic pressure modulate renal sodium and water excretion and systemic blood pressure. Recently we have demonstrated that the electrogenic sodium bicarbonate cotransporter, NBC4c, first cloned in our laboratory and encoded by the SLC4A5 gene is specifically expressed in the mammalian kidney on the apical membrane of uroepithelial cells lining the renal pelvis. Recent linkage analysis studies in humans have implicated SLC4A5 as a candidate hypertension- susceptibility gene, suggesting an important and as yet uncharacterized role for NBC4c in blood pressure control. We hypothesized that NBC4c plays a key role in the reflex modulation of renal sodium and water excretion in response to changes in renal pelvic hydrostatic pressure. In preliminary experiments, an increase in hydrostatic pressure stimulated the flux through NBC4c in renal pelvic uroepithelial cells. In this first part of this proposal, we will characterize the signaling pathway(s) involved in the stimulation of NBC4c-mediated transport in uroepithelial cells. In the second part of this proposal, we will study the pathways involved in switching off the signaling cascade. In particular, the specific role of the calcium-dependent phosphatase calcineurin will be studied. This proposal will enhance our understanding of the biology of sodium bicarbonate cotransport in the renal pelvis and its important physiological role in sodium and water homeostasis in the kidney and whole organism. Public Health Relevance Statement High blood pressure (hypertension) is an important cause of heart, brain and kidney disease in the United States. Recent studies have implicated NBC4 as a new candidate protein that is associated with high blood pressure however the mechanism is entirely unknown. The results of the studies in this proposal will lead to an increased understanding of the role that NBC4 plays in blood pressure control and potentially lead to important new approaches for treating high blood pressure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK058563-10
Application #
8134437
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Ketchum, Christian J
Project Start
2001-03-01
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
10
Fiscal Year
2011
Total Cost
$314,323
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Kurtz, Ira (2014) NBCe1 as a model carrier for understanding the structure-function properties of Na? -coupled SLC4 transporters in health and disease. Pflugers Arch 466:1501-16
Zhu, Quansheng; Liu, Weixin; Kao, Liyo et al. (2013) Topology of NBCe1 protein transmembrane segment 1 and structural effect of proximal renal tubular acidosis (pRTA) S427L mutation. J Biol Chem 288:7894-906
Lacruz, R S; Smith, C E; Kurtz, I et al. (2013) New paradigms on the transport functions of maturation-stage ameloblasts. J Dent Res 92:122-9
Zhu, Quansheng; Shao, Xuesi M; Kao, Liyo et al. (2013) Missense mutation T485S alters NBCe1-A electrogenicity causing proximal renal tubular acidosis. Am J Physiol Cell Physiol 305:C392-405
Jiang, Jiansen; Magilnick, Nathaniel; Tsirulnikov, Kirill et al. (2013) Single particle electron microscopy analysis of the bovine anion exchanger 1 reveals a flexible linker connecting the cytoplasmic and membrane domains. PLoS One 8:e55408
Kurtz, Ira; Zhu, Quansheng (2013) Structure, function, and regulation of the SLC4 NBCe1 transporter and its role in causing proximal renal tubular acidosis. Curr Opin Nephrol Hypertens 22:572-83
Burette, Alain C; Weinberg, Richard J; Sassani, Patrick et al. (2012) The sodium-driven chloride/bicarbonate exchanger in presynaptic terminals. J Comp Neurol 520:1481-92
Lacruz, Rodrigo S; Smith, Charles E; Moffatt, Pierre et al. (2012) Requirements for ion and solute transport, and pH regulation during enamel maturation. J Cell Physiol 227:1776-85
Kao, Liyo; Abuladze, Natalia; Shao, Xuesi M et al. (2012) A new technique for multiple re-use of planar patch clamp chips. J Neurosci Methods 208:205-10
Sergeev, Mikhail; Godin, Antoine G; Kao, Liyo et al. (2012) Determination of membrane protein transporter oligomerization in native tissue using spatial fluorescence intensity fluctuation analysis. PLoS One 7:e36215

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