The long term goals of this project are to determine the regulation of ion channels in the kidney and to integrate our findings to kidney diseases. This proposal will determine how the renal epithelial sodium channel (ENaC) is regulated by ATP-binding cassette transporter A1 (ABCA1). The proposed in vivo and in vitro experiments will test a central hypothesis that deletion of ABCA1 elevates Cho in cortical collecting duct (CCD) principal cells, this elevated Cho stabilizes phosphatidylinositol-4,5-bisphosphate (PIP2) in apical microvilli, and this microvilli- located PIP2 increases ENaC activity to enhance sodium retention and cause hypertension. The hypothesis is based on previous studies and two key preliminary data showing that both blood pressure and ENaC activity are elevated in ABCA1 KO mice and that inhibition of Cho synthesis causes PIP2 diffusion out of microvilli and reduces ENaC activity. The proposal is clinically significant, because investigation of ABCA1-controlled membrane and intracellular Cho homeostasis may provide a rationale for using Cho biosynthesis inhibitors such as statins to treat hypertension. The project is innovative because it will provide the first evidence for the role of ABCA1 in regulating ENaC activity and PIP2 lateral movement between two specialized apical membrane domains (microvilli and planar regions). A variety of experimental approaches including scanning ion conductance microscopy and the high resolution scanning patch-clamp techniques will be used to test three hypotheses (1) that deletion of ABCA1 increases ENaC activity and Na+ absorption thereby causing hypertension;(2) that Cho increases ENaC activity by stabilizing PIP2 in microvilli;and (3) that PIP2 in planar regions promotes formation of endocytic pits containing inactive ENaC.

Public Health Relevance

The project aims at investigating whether a cholesterol transporter regulates the renal epithelial sodium channel and thereby affecting blood pressure through a pathway associated with a localized membrane lipid.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (KMBD)
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Ketchum, Christian J
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Emory University
Schools of Medicine
United States
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Zhai, Yu-Jia; Liu, Bing-Chen; Wei, Shi-Peng et al. (2018) Depletion of Cholesterol Reduces ENaC Activity by Decreasing Phosphatidylinositol-4,5-Bisphosphate in Microvilli. Cell Physiol Biochem 47:1051-1059
Zou, Li; Linck, Valerie; Zhai, Yu-Jia et al. (2018) Knockout of mitochondrial voltage-dependent anion channel type 3 increases reactive oxygen species (ROS) levels and alters renal sodium transport. J Biol Chem 293:1666-1675
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Liang, Chen; Wang, Qiu-Shi; Yang, Xu et al. (2018) Oxidized low-density lipoprotein stimulates epithelial sodium channels in endothelial cells of mouse thoracic aorta. Br J Pharmacol 175:1318-1328
Wynne, Brandi M; Zou, Li; Linck, Valerie et al. (2017) Regulation of Lung Epithelial Sodium Channels by Cytokines and Chemokines. Front Immunol 8:766
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
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Zheng, Wei-Wan; Li, Xin-Yuan; Liu, Hui-Bin et al. (2016) AMP-Activated Protein Kinase Attenuates High Salt-Induced Activation of Epithelial Sodium Channels (ENaC) in Human Umbilical Vein Endothelial Cells. Oxid Med Cell Longev 2016:1531392
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Thai, Tiffany L; Yu, Ling; Galarza-Paez, Laura et al. (2015) The Polarized Effect of Intracellular Calcium on the Renal Epithelial Sodium Channel Occurs as a Result of Subcellular Calcium Signaling Domains Maintained by Mitochondria. J Biol Chem 290:28805-11

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