Na-coupled HCO3 transporters share similarities with AE isoforms (i.e. transport of HCO3 and sensitivity to inhibition by DIDS) indicating structural homology with each other. They have cloned the human kidney Na:HCO3 cotransporter (NBC-1) based on homology with the AE family. NBC-1 is 7.6 kb, encodes a protein with an apparent MW of 116 kD, and contains consensus binding sites for PKA, PKC, and Casein kinase II. Functional data support the presence of more than one isoform of NBC (e.e. kidney versus liver) and this is confirmed by the abundance of NBC-1 mRNA in the kidney and its absence in the liver and stomach. The purpose of the current proposal is to clone and characterize the Na-coupled HCO3 transporters (NBC isoforms and Na-dependent Cl/HCO3 exchange) in mammalian tissues.
The Specific Aims of this proposal include: 1. Cloning and functional expression of Na-coupled HCO3 transporters; 2. Characterization and regulation of Na-coupled HCO3 transporters in acute and chronic states; and 3. Examining structure-function relationship of NBC-1.
Aim 1) They plan to clone the Na-dependent Cl/HCO3 exchanger and NBC isoforms and express them in cultured HEK293 cells. The work on these areas is in progress.
Aim 2) They will characterize NBC-1 (and NBC isoforms) with respect to stoichiometry, inhibitory profile, ion specificity and examine its acute regulation by phosphatase and kinase pathways in transfected cells. Chronic regulation of NBC-1 will be examined by mRNA and protein abundance in acid-base disorders.
Aim 3) They will examine the effect of progressive DNA truncation (on the C-terminal) region on pHi sensitivity and regulation of NBC-1 in cells transfected with mutant cDNAs. Insight into regulation and gene structure of Na-coupled HCO3 transporters should enhance our knowledge on cell regulation and acid-base homeostasis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK054430-01
Application #
2686271
Study Section
General Medicine B Study Section (GMB)
Project Start
1998-09-01
Project End
2002-08-31
Budget Start
1998-09-01
Budget End
1999-08-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Soleimani, Manoocher; Xu, Jie (2006) SLC26 chloride/base exchangers in the kidney in health and disease. Semin Nephrol 26:375-85
Wilke, Catherine; Sheriff, Sulaiman; Soleimani, Manoocher et al. (2005) Vasopressin-independent regulation of collecting duct aquaporin-2 in food deprivation. Kidney Int 67:201-16
Xu, Jie; Henriksnas, Johanna; Barone, Sharon et al. (2005) SLC26A9 is expressed in gastric surface epithelial cells, mediates Cl-/HCO3- exchange, and is inhibited by NH4+. Am J Physiol Cell Physiol 289:C493-505
Dou, Hongwei; Xu, Jie; Wang, Zhaohui et al. (2004) Co-expression of pendrin, vacuolar H+-ATPase alpha4-subunit and carbonic anhydrase II in epithelial cells of the murine endolymphatic sac. J Histochem Cytochem 52:1377-84
Barone, Sharon; Amlal, Hassane; Xu, Jie et al. (2004) Differential regulation of basolateral Cl-/HCO3- exchangers SLC26A7 and AE1 in kidney outer medullary collecting duct. J Am Soc Nephrol 15:2002-11
Petrovic, Snezana; Barone, Sharon; Xu, Jie et al. (2004) SLC26A7: a basolateral Cl-/HCO3- exchanger specific to intercalated cells of the outer medullary collecting duct. Am J Physiol Renal Physiol 286:F161-9
Petrovic, Snezana; Barone, Sharon; Weinstein, Alan M et al. (2004) Activation of the apical Na+/H+ exchanger NHE3 by formate: a basis of enhanced fluid and electrolyte reabsorption by formate in the kidney. Am J Physiol Renal Physiol 287:F336-46
Amlal, Hassane; Sheriff, Sulaiman; Soleimani, Manoocher (2004) Upregulation of collecting duct aquaporin-2 by metabolic acidosis: role of vasopressin. Am J Physiol Cell Physiol 286:C1019-30
Soleimani, M (2003) Functional and molecular properties of Na+:HCO-3 cotransporters (NBC). Minerva Urol Nefrol 55:131-40
Xu, Jie; Wang, Zhaohui; Barone, Sharone et al. (2003) Expression of the Na+-HCO-3 cotransporter NBC4 in rat kidney and characterization of a novel NBC4 variant. Am J Physiol Renal Physiol 284:F41-50

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