Both the gastric (g) and colonic (c) isoforms of H+/K+-ATPase (HKA) are expressed at low levels in renal collecting duct (CD) cells but the functional role(s) for these HKA remain uncertain. They propose that cHKA specifically plays a pivotal role in renal HCO3-, K+ and Na+ transport in several pathophysiologic states. Our studies show that cHKA mRNA and or activity is increased in conditions associated with increased HCO3- delivery to the CD (proximal RTA) or in potassium depletion (KD). Interestingly, hypophysectomy (HPX) suppresses increased expression of cHKA in KD but not in proximal RTA. They hypothesize that cHKA is vital to acid-base, K+ and Na+ homeostasis: Upregulation of cHKA blunts HCO3- loss in instances of increased delivery of HCO3- to the distal nephron and accelerates K+ and Na+ reabsorption in KD. To elucidate this hypothesis, we propose to examine the molecular and functional regulation of cHKA in: a) three models associated with increased delivery of HCO3- to the distal tubule but different states of acid-base balance: acetazolamide (acidosis), chloride depletion (alkalosis), and NaHCO3 loading (normal); and b) in potassium depletion. Acid-base and electrolyte changes, HCO3-reabsorption in isolated perfused CCD and OMCD, and cortical, medullary, and nephron-segment mRNA and protein for cHKA will be determined in rats and mice (both cHKA-deficient transgenic and wild-type) with KD or increased HCO3-delivery to distal tubules. In KD rats experiments will be repeated in HPX + hormonal replacement. Lastly, they will examine transcriptional regulation of cHKA. Mice transgenic for a cHKA promoter-luciferase reporter (PLR) construct will be studied in the above models. Coupled with the data from (a) and (b) above, these studies suggest possible signals for study in cultured renal cells. These will be transiently transfected with deleting constructs of LR and studied under in vitro conditions to determine the sensing elements within the promoter of cHKA cDNA. Insight into regulation of cHKA will significantly enhance our knowledge on a variety of pathologic conditions associated with electrolyte and acid-base abnormalities.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052821-03
Application #
6178091
Study Section
General Medicine B Study Section (GMB)
Program Officer
Scherbenske, M James
Project Start
1998-06-08
Project End
2002-05-31
Budget Start
2000-06-01
Budget End
2001-05-31
Support Year
3
Fiscal Year
2000
Total Cost
$192,688
Indirect Cost
Name
University of Cincinnati
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Petrovic, Snezana; Wang, Zhaohui; Ma, Liyun et al. (2003) Regulation of the apical Cl-/HCO-3 exchanger pendrin in rat cortical collecting duct in metabolic acidosis. Am J Physiol Renal Physiol 284:F103-12
Wang, Zhaohui; Petrovic, Snezana; Mann, Elizabeth et al. (2002) Identification of an apical Cl(-)/HCO3(-) exchanger in the small intestine. Am J Physiol Gastrointest Liver Physiol 282:G573-9
Soleimani, Manoocher (2002) Na+:HCO3- cotransporters (NBC): expression and regulation in the kidney. J Nephrol 15 Suppl 5:S32-40
Petrovic, Snezana; Spicer, Zachary; Greeley, Tracey et al. (2002) Novel Schering and ouabain-insensitive potassium-dependent proton secretion in the mouse cortical collecting duct. Am J Physiol Renal Physiol 282:F133-43
Amlal, H; Chen, Q; Habo, K et al. (2001) Fasting downregulates renal water channel AQP2 and causes polyuria. Am J Physiol Renal Physiol 280:F513-23
Sarangarajan, R; Shumaker, H; Soleimani, M et al. (2001) Molecular and functional characterization of sodium--hydrogen exchanger in skin as well as cultured keratinocytes and melanocytes. Biochim Biophys Acta 1511:181-92
Soleimani, M; Burnham, C E (2001) Na+:HCO(3-) cotransporters (NBC): cloning and characterization. J Membr Biol 183:71-84
Greeley, T; Shumaker, H; Wang, Z et al. (2001) Downregulated in adenoma and putative anion transporter are regulated by CFTR in cultured pancreatic duct cells. Am J Physiol Gastrointest Liver Physiol 281:G1301-8
Ali, R; Amlal, H; Burnham, C E et al. (2000) Glucocorticoids enhance the expression of the basolateral Na+:HCO3- cotransporter in renal proximal tubules. Kidney Int 57:1063-71
Soleimani, M; Burnham, C E (2000) Physiologic and molecular aspects of the Na+:HCO3- cotransporter in health and disease processes. Kidney Int 57:371-84

Showing the most recent 10 out of 23 publications