Palmitate Stimulates the Epithelial Sodium Channel by Elevating Intracellular Calcium, Reactive Oxygen Species, and Phosphoinositide 3-Kinase Activity

• Type of Material: Article
• Authors: Qiu-Shi Wang, Harbin Medical University; Chen Liang, Harbin Medical University; Na Niu, Harbin Medical University; Xu Yang, Harbin Medical University; Xiao Chen, Harbin Medical University; Bin-Lin Song, Harbin Medical University; Chang-Jiang Yu, Harbin Medical University; Ming-Ming Wu, Harbin Medical University; Zhi-Ren Zhang, Harbin Medical University; He-Ping Ma, Emory University
• Language: English
• Date: 2018-01-01
• Publisher: Hindawi Publishing Corporation
• Publication Version: Final Published Version
• Copyright Statement: © 2018 Qiu-Shi Wang et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1155/2018/7560610
• Title of Journal or Parent Work: Oxidative Medicine and Cellular Longevity
• ISSN: 1942-0900
• Volume: 2018
• Start Page: 7560610
• End Page: 7560610
• Grant/Funding Information: This study was supported by the Key Project of the Chinese National Program for Fundamental Research and Development (973 Program 2014CB542401 to Z-RZ), the National Natural Science Foundation of China (91639202 and 81320108002 to Z-RZ and 81600221 to Q-SW), a grant from NIH (R01 DK 100582 to H-PM), and the Natural Science Foundation of Heilongjiang Province (QC2016128 to Q-SW).
• Keywords: Science & Technology; ENAC; AMILORIDE; ALPHA; APOPTOSIS; GLUCOSE; RECEPTOR; EXCRETION; Cell Biology; BETA; NA+; FREE FATTY-ACID; Life Sciences & Biomedicine
• Research Categories: Biology, Cell; Biology, Physiology; Health Sciences, Pharmacy

Abstract

Previous studies indicate that the epithelial sodium channel (ENaC) in the kidney is upregulated in diabetes mellitus. Here, we show that ENaC single-channel activity in distal nephron cells was significantly increased by palmitate, a free fatty acid which is elevated in diabetes mellitus. We also show that palmitate increased intracellular Ca 2+ and that after chelating intracellular Ca 2+ with BAPTA-AM, palmitate failed to affect ENaC activity. Treatment of the cells with 2-aminoethoxydiphenyl borate (2-APB, an inhibitor of IP 3 receptors) abolished the elevation of both intracellular Ca 2+ and ENaC activity. Treatment of the cells with apocynin (an NADPH oxidase inhibitor), dithiothreitol/NaHS (reducing agents), or LY294002 (a phosphoinositide 3-kinase (PI3K) inhibitor) prevented palmitate-induced ENaC activity, whereas thimerosal (an oxidizing agent) mimicked the effects of palmitate on ENaC activity. However, these treatments did not alter the levels of intracellular Ca 2+ , indicating that elevation of reactive oxygen species (ROS) and activation of PI3K are downstream of the signaling cascade. Since we have shown that ROS stimulate ENaC by activating PI3K, these data together suggest that palmitate first elevates intracellular Ca 2+ , then activates an NADPH oxidase to elevate intracellular ROS and PI3K activity, and finally increases ENaC activity via the activated PI3K.