One of the primary functions of the proximal tubule is to absorb NaCl. Formate, PTH and angiotensin II are potent regulators of proximal tubule NaCl transport. Regulation of NaCl transport by formate in the proximal straight tubule is currently believed to be mediated by apical Cl-/formate exchange coupled to Na+/H+ exchange with apical formic acid recycling. However, the transport properties of the rabbit proximal straight tubule characterized by their laboratory do not support this model. In the rabbit superficial S2 proximal straight tubule, apical Cl-/base exchange occurs in the absence of exogenous formate and bicarbonate, and is stimulated by Na+ removal. The data suggest that this transporter functions in a Cl/OH- mode. Na+ removal appears to regulate apical Cl-/base exchange via a change in intracellular Ca2+. S2 tubule formate production and blood formate concentration are too low to permit significant apical formic recycling yet it is generally agreed that luminal formate stimulates the transepithelial NaCl absorption. In this proposal, the data by the principal investigator demonstrates that luminal formate stimulates the apical Na+/H+ exchange activity directly. The principal investigator also shows evidence that PTH and AII regulate apical/basolateral anion exchange and Cl- transport in the proximal straight tubule. The following hypotheses will be tested in this proposal: 1) apical NaCl uptake is mediated predominantly by Na+/H+ exchange coupled to Cl-/base exchange; 2) Na+ removal regulates apical Cl-/base exchange through an increase in intracellular Ca2+ via a calmodulin-dependent mechanism; 3) Luminal formate increases transepithelial NaCl transport by stimulating the apical Na+/H+ exchange and not via formate-dependent Cl-/base exchange; 4) Basolateral formate decreases transepithelial NaCl transport by stimulating the basolateral Na+/H+ exchange; and 5) PTH and AII regulate apical and basolateral anion exchange and Cl- transport in the proximal tubule.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK046976-02
Application #
2701133
Study Section
Special Emphasis Panel (ZRG4-GMB (01))
Project Start
1997-05-20
Project End
2001-04-30
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Gross, Eitan; Kurtz, Ira (2002) Structural determinants and significance of regulation of electrogenic Na(+)-HCO(3)(-) cotransporter stoichiometry. Am J Physiol Renal Physiol 283:F876-87
Sassani, Pejvak; Pushkin, Alexander; Gross, Eitan et al. (2002) Functional characterization of NBC4: a new electrogenic sodium-bicarbonate cotransporter. Am J Physiol Cell Physiol 282:C408-16
Gross, E; Abuladze, N; Pushkin, A et al. (2001) The stoichiometry of the electrogenic sodium bicarbonate cotransporter pNBC1 in mouse pancreatic duct cells is 2 HCO(3)(-):1 Na(+). J Physiol 531:375-82
Gross, E; Hawkins, K; Abuladze, N et al. (2001) The stoichiometry of the electrogenic sodium bicarbonate cotransporter NBC1 is cell-type dependent. J Physiol 531:597-603
Luo, X; Choi, J Y; Ko, S B et al. (2001) HCO3- salvage mechanisms in the submandibular gland acinar and duct cells. J Biol Chem 276:9808-16
Gross, E; Hawkins, K; Pushkin, A et al. (2001) Phosphorylation of Ser(982) in the sodium bicarbonate cotransporter kNBC1 shifts the HCO(3)(-) : Na(+) stoichiometry from 3 : 1 to 2 : 1 in murine proximal tubule cells. J Physiol 537:659-65
Bok, D; Schibler, M J; Pushkin, A et al. (2001) Immunolocalization of electrogenic sodium-bicarbonate cotransporters pNBC1 and kNBC1 in the rat eye. Am J Physiol Renal Physiol 281:F920-35
Pushkin, A; Abuladze, N; Newman, D et al. (2000) Cloning, characterization and chromosomal assignment of NBC4, a new member of the sodium bicarbonate cotransporter family. Biochim Biophys Acta 1493:215-8
Pushkin, A V; Tsuprun, V L; Abuladze, N K et al. (2000) Oligomeric structure of bAE3 protein. IUBMB Life 50:397-401
Kwon, T H; Pushkin, A; Abuladze, N et al. (2000) Immunoelectron microscopic localization of NBC3 sodium-bicarbonate cotransporter in rat kidney. Am J Physiol Renal Physiol 278:F327-36

Showing the most recent 10 out of 21 publications