Hypertension, which is a major risk factor for stroke and heart attack, affects nearly one out of every three US adults. Several lines of evidence suggest that reactive oxygen species (ROS) plays a very important role in the salt-sensitive hypertension, by targeting both cardiovascular system and the kidney. It is known that elevated activity of the epithelial sodium channel (ENaC) can lead to hypertension. However, whether ENaC contributes to salt-sensitive hypertension remains completely unknown. Therefore, understanding the role of ROS, especially hydrogen peroxide (H2O2) produced in the cell, in regulating ENaC should provide important information for the treatment of hypertension. With the previous R01 support, we have published 10 peer- reviewed articles and concluded that anionic phospholipids including phophatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3) elevates ENaC activity and apical expression. Our preliminary results suggest a hypothesis that ROS (particularly H2O2) is elevated in the distal nephron cells due to high salt intake, elevates PI(3,4,5)P3, and stimulates ENaC. The present proposal will test this hypothesis by performing both in vitro and in vivo experiments. The first specific aim is to determine the mechanism by which ROS stimulates ENaC. The second specific aim is to determine whether the mechanism by which high salt intake paradoxically stimulates ENaC by elevating ROS in the distal nephron cells of salt-sensitive rats. These studies should provide additional information for the pathogenesis of salt-sensitive hypertension

Public Health Relevance

Hypertension affects nearly one out of every three US adults. The present proposal will use both cultured cells and a salt-sensitive rat model to determine how high salt diet causes hypertension. The study will focus on the role of the epithelial sodium channel and reactive oxygen species in the kidney.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK067110-05A2
Application #
7889643
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Ketchum, Christian J
Project Start
2004-07-01
Project End
2013-08-31
Budget Start
2010-09-30
Budget End
2011-08-31
Support Year
5
Fiscal Year
2010
Total Cost
$232,500
Indirect Cost
Name
Emory University
Department
Physiology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Yang, Li-Li; Liu, Bing-Chen; Lu, Xiao-Yu et al. (2017) Inhibition of TRPC6 reduces non-small cell lung cancer cell proliferation and invasion. Oncotarget 8:5123-5134
Alli, Abdel A; Bao, Hui-Fang; Liu, Bing-Chen et al. (2015) Calmodulin and CaMKII modulate ENaC activity by regulating the association of MARCKS and the cytoskeleton with the apical membrane. Am J Physiol Renal Physiol 309:F456-63
Liu, Yingli; Song, Xiang; Shi, Yanling et al. (2015) WNK1 activates large-conductance Ca2+-activated K+ channels through modulation of ERK1/2 signaling. J Am Soc Nephrol 26:844-54
Liu, Bing-Chen; Yang, Li-Li; Lu, Xiao-Yu et al. (2015) Lovastatin-Induced Phosphatidylinositol-4-Phosphate 5-Kinase Diffusion from Microvilli Stimulates ROMK Channels. J Am Soc Nephrol 26:1576-87
Lu, Xiao-Yu; Liu, Bing-Chen; Wang, Li-Hua et al. (2015) Acute ethanol induces apoptosis by stimulating TRPC6 via elevation of superoxide in oxygenated podocytes. Biochim Biophys Acta 1853:965-74
Reifenberger, Matthew S; Yu, Ling; Bao, Hui-Fang et al. (2014) Cytochalasin E alters the cytoskeleton and decreases ENaC activity in Xenopus 2F3 cells. Am J Physiol Renal Physiol 307:F86-95
Song, Xiang; Liu, Bing-Chen; Lu, Xiao-Yu et al. (2014) Lovastatin inhibits human B lymphoma cell proliferation by reducing intracellular ROS and TRPC6 expression. Biochim Biophys Acta 1843:894-901
Bao, Hui-Fang; Thai, Tiffany L; Yue, Qiang et al. (2014) ENaC activity is increased in isolated, split-open cortical collecting ducts from protein kinase C? knockout mice. Am J Physiol Renal Physiol 306:F309-20
Liu, Bing-Chen; Song, Xiang; Lu, Xiao-Yu et al. (2013) Lovastatin attenuates effects of cyclosporine A on tight junctions and apoptosis in cultured cortical collecting duct principal cells. Am J Physiol Renal Physiol 305:F304-13
Liu, Bing-Chen; Song, Xiang; Lu, Xiao-Yu et al. (2013) High glucose induces podocyte apoptosis by stimulating TRPC6 via elevation of reactive oxygen species. Biochim Biophys Acta 1833:1434-42

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