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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Cellular and Molecular Biology of the Kidney Study Section (CMBK)
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Ketchum, Christian J
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Emory University
Schools of Medicine
United States
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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
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
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Zhang, Zhi-Ren; Chou, Chu-Fang; Wang, Jing et al. (2010) Anionic phospholipids differentially regulate the epithelial sodium channel (ENaC) by interacting with alpha, beta, and gamma ENaC subunits. Pflugers Arch 459:377-87
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