The main goal of the present proposal is to explore the mechanism by which the proteintyrosine kinase (PTK)-dependent signal transduction pathway mediates the inhibitory effect of a low dietary K+ intake on K+ secretion. Kidney plays a key role in maintaining K+ homeostasis. A high plasma K+ (hyperkalemia) or a low plasma K+ (hypokalemia) could have serious and life threatening consequences. The cortical collecting duct (CCD) is responsible for the final and fine regulation of K+ secretion. K+ secretion is regulated by a variety of factors, such as hormones and K+ diet. The dietary K+ intake is the most important factor which regulates renal K+ secretion: a high K+ intake increases whereas a low K+ intake decreases the renal K+ secretion. The effect of the dietary K+ intake on K+ secretion is partially achieved by changing the number of functional ROMK-like small conductance K+ (SK) channels in the apical membrane of the CCD. It has been demonstrated that a high K+ intake increases whereas a low K+ intake decreases the number of the SK channels in the apical membrane of the CCD. A large body of evidence indicates that PTK plays a key role in mediating the effect of dietary K+ intake on ROMK-like SK channels in the CCD. However, the mechanism by which a low K+ intake increases the PTK expression and PTK activity is not understood. Our preliminary data have strongly suggested that superoxide anions (O2-) and the related product may be responsible for increase in expression of Src-family PTK induced by low dietary K+ intake. In the present proposal, the hypothesis that O2- and the related products are the upstream signals of PTK-dependent pathways responsible for mediating the effect of low K+ intake on ROMK1 will be tested with optical, molecular and electrophysiological approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK047402-12
Application #
6838821
Study Section
General Medicine B Study Section (GMB)
Program Officer
Ketchum, Christian J
Project Start
1994-01-01
Project End
2007-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
12
Fiscal Year
2005
Total Cost
$308,880
Indirect Cost
Name
New York Medical College
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041907486
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Wei, Yuan; Liao, Yi; Zavilowitz, Beth et al. (2014) Angiotensin II type 2 receptor regulates ROMK-like K? channel activity in the renal cortical collecting duct during high dietary K? adaptation. Am J Physiol Renal Physiol 307:F833-43
Jin, Yan; Wang, Yan; Wang, Zhi-Jian et al. (2009) Inhibition of angiotensin type 1 receptor impairs renal ability of K conservation in response to K restriction. Am J Physiol Renal Physiol 296:F1179-84
Wang, Wen-Hui; Giebisch, Gerhard (2009) Regulation of potassium (K) handling in the renal collecting duct. Pflugers Arch 458:157-68
Muto, Shigeaki; Tsuruoka, Shuichi; Miyata, Yukio et al. (2009) Basolateral Na+/H+ exchange maintains potassium secretion during diminished sodium transport in the rabbit cortical collecting duct. Kidney Int 75:25-30
Wei, Yuan; Zavilowitz, Beth; Satlin, Lisa M et al. (2007) Angiotensin II inhibits the ROMK-like small conductance K channel in renal cortical collecting duct during dietary potassium restriction. J Biol Chem 282:6455-62
Babilonia, Elisa; Li, Dimin; Wang, Zhijian et al. (2006) Mitogen-activated protein kinases inhibit the ROMK (Kir 1.1)-like small conductance K channels in the cortical collecting duct. J Am Soc Nephrol 17:2687-96
Babilonia, Elisa; Wei, Yuan; Sterling, Hyacinth et al. (2005) Superoxide anions are involved in mediating the effect of low K intake on c-Src expression and renal K secretion in the cortical collecting duct. J Biol Chem 280:10790-6
Sterling, Hyacinth; Lin, Dao-Hong; Chen, Yu-Jung et al. (2004) PKC expression is regulated by dietary K intake and mediates internalization of SK channels in the CCD. Am J Physiol Renal Physiol 286:F1072-8
Lin, Dao-Hong; Sterling, Hyacinth; Yang, Baofeng et al. (2004) Protein tyrosine kinase is expressed and regulates ROMK1 location in the cortical collecting duct. Am J Physiol Renal Physiol 286:F881-92
Sterling, Hyacinth; Lin, Dao-Hong; Gu, Rui-Min et al. (2002) Inhibition of protein-tyrosine phosphatase stimulates the dynamin-dependent endocytosis of ROMK1. J Biol Chem 277:4317-23

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