The kidney assumes a critical role in the maintenance of acid-base balance, extracellular fluid volume and blood pressure homeostasis via regulation of NaHCO3 and NaCI excretion. One protein that is central to all these processes is the Na/H exchanger isoform 3 (NHE3). NHE3 mediates a great majority of NaHCO3 and NaCI absorption and is regulated rapidly by hemodynamic and neurohumoral factors to match the demands of the organism. Recent work from several laboratories have shown that NHE3 can be acutely regulated via a number O mechanisms. We have shown that hormones such as parathyroid hormone (PTH) and dopamine (DA) acutely inhibits NHE3 transport activity without changing its protein abundance on the plasma membrane. This inhibition is associated with complex changes in NHE3 phosphorylation and clustering of NHE3 proteins. We hypothesize that changes in NHE3 phosphorylation leads to NHE3 clustering which results in inhibition of activity. In this proposal. we will focus on: 1. Mapping out the amino acid residues n NHE3 that is regulated. 2. Determine whether changes in NHE3 phosphorylation per se alters its activity. 3. Determine whether NHE3 clustering is a consequence of changes in NHE3 phosphorylation and whether NHE3 clustering alters its activity. 4. Determine the role of two NHE3 binding proteins in mediating NHE3 clustering and changes in phosphorylation. We will apply protocols in transport physiology, biochemistry, recombinant DNA technology, immunohistology, and biophysical fluorescence spectroscopy to study whole animals, culture cells, and purified proteins. These studies will uncover highly fundamental mechanisms of regulation of an important epithelial Na transporter and further our understanding 01 disturbance in acid-base balance, Na retention and hypertension.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK048482-08
Application #
6635029
Study Section
General Medicine B Study Section (GMB)
Program Officer
Star, Robert A
Project Start
1995-02-01
Project End
2006-01-31
Budget Start
2003-04-01
Budget End
2004-01-31
Support Year
8
Fiscal Year
2003
Total Cost
$259,350
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Hu, Ming Chang; Di Sole, Francesca; Zhang, Jianning et al. (2013) Chronic regulation of the renal Na(+)/H(+) exchanger NHE3 by dopamine: translational and posttranslational mechanisms. Am J Physiol Renal Physiol 304:F1169-80
Hedayati, S Susan; Minhajuddin, Abu T; Ijaz, Adeel et al. (2012) Association of urinary sodium/potassium ratio with blood pressure: sex and racial differences. Clin J Am Soc Nephrol 7:315-22
Di Sole, F; Hu, Ming-Chang; Zhang, Jianning et al. (2011) The reduction of Na/H exchanger-3 protein and transcript expression in acute ischemia-reperfusion injury is mediated by extractable tissue factor(s). Kidney Int 80:822-831
Hu, Ming Chang; Shi, Mingjun; Zhang, Jianning et al. (2011) Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol 22:124-36
Goetz, Regina; Nakada, Yuji; Hu, Ming Chang et al. (2010) Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation. Proc Natl Acad Sci U S A 107:407-12
Bobulescu, I Alexandru; QuiƱones, Henry; Gisler, Serge M et al. (2010) Acute regulation of renal Na+/H+ exchanger NHE3 by dopamine: role of protein phosphatase 2A. Am J Physiol Renal Physiol 298:F1205-13
Hu, Ming-Chang; Shi, Mingjun; Zhang, Jianning et al. (2010) Klotho deficiency is an early biomarker of renal ischemia-reperfusion injury and its replacement is protective. Kidney Int 78:1240-51
Hu, Ming-Chang; Kuro-o, Makoto; Moe, Orson W (2010) Klotho and kidney disease. J Nephrol 23 Suppl 16:S136-44
Hu, Ming Chang; Shi, Mingjun; Zhang, Jianning et al. (2010) Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB J 24:3438-50
Di Sole, Francesca; Babich, Victor; Moe, Orson W (2009) The calcineurin homologous protein-1 increases Na(+)/H(+) -exchanger 3 trafficking via ezrin phosphorylation. J Am Soc Nephrol 20:1776-86

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