PMID- 34122084 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240505 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 12 DP - 2021 TI - NaHS or Lovastatin Attenuates Cyclosporine A-Induced Hypertension in Rats by Inhibiting Epithelial Sodium Channels. PG - 665111 LID - 10.3389/fphar.2021.665111 [doi] LID - 665111 AB - The use of cyclosporine A (CsA) in transplant recipients is limited due to its side effects of causing severe hypertension. We have previously shown that CsA increases the activity of the epithelial sodium channel (ENaC) in cultured distal nephron cells. However, it remains unknown whether ENaC mediates CsA-induced hypertension and how we could prevent hypertension. Our data show that the open probability of ENaC in principal cells of split-open cortical collecting ducts was significantly increased after treatment of rats with CsA; the increase was attenuated by lovastatin. Moreover, CsA also elevated the levels of intracellular cholesterol (Cho), intracellular reactive oxygen species (ROS) via activation of NADPH oxidase p47(phox), serum- and glucocorticoid-induced kinase isoform 1 (Sgk1), and phosphorylated neural precursor cell-expressed developmentally downregulated protein 4-2 (p-Nedd4-2) in the kidney cortex. Lovastatin also abolished CsA-induced elevation of alpha-, ss-, and gamma-ENaC expressions. CsA elevated systolic blood pressure in rats; the elevation was completely reversed by lovastatin (an inhibitor of cholesterol synthesis), NaHS (a donor of H(2)S which ameliorated CsA-induced elevation of reactive oxygen species), or amiloride (a potent ENaC blocker). These results suggest that CsA elevates blood pressure by increasing ENaC activity via a signaling cascade associated with elevation of intracellular ROS, activation of Sgk1, and inactivation of Nedd4-2 in an intracellular cholesterol-dependent manner. Our data also show that NaHS ameliorates CsA-induced hypertension by inhibition of oxidative stress. CI - Copyright (c) 2021 Wang, Liang, Jiang, Zhu, Sun, Niu, Yang, Yang, Dong, Yao, Yu, Lou, Tang, Wu, Zhang and Ma. FAU - Wang, Qiu-Shi AU - Wang QS AD - Departments of Pharmacy and Cardiology, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Heilongjiang key laboratory for Metabolic disorder & cancer related cardiovascular diseases, NHC Key Laboratory of Cell Transplantation, Harbin Medical University & Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, China. AD - Department of Physiology, Emory University School of Medicine, Atlanta, GA, United States. FAU - Liang, Chen AU - Liang C AD - Departments of Pharmacy and Cardiology, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Heilongjiang key laboratory for Metabolic disorder & cancer related cardiovascular diseases, NHC Key Laboratory of Cell Transplantation, Harbin Medical University & Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, China. FAU - Jiang, Shuai AU - Jiang S AD - Departments of Pharmacy and Cardiology, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Heilongjiang key laboratory for Metabolic disorder & cancer related cardiovascular diseases, NHC Key Laboratory of Cell Transplantation, Harbin Medical University & Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, China. FAU - Zhu, Di AU - Zhu D AD - Departments of Pharmacy and Cardiology, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Heilongjiang key laboratory for Metabolic disorder & cancer related cardiovascular diseases, NHC Key Laboratory of Cell Transplantation, Harbin Medical University & Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, China. FAU - Sun, Yu AU - Sun Y AD - Departments of Pharmacy and Cardiology, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Heilongjiang key laboratory for Metabolic disorder & cancer related cardiovascular diseases, NHC Key Laboratory of Cell Transplantation, Harbin Medical University & Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, China. FAU - Niu, Na AU - Niu N AD - Departments of Pharmacy and Cardiology, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Heilongjiang key laboratory for Metabolic disorder & cancer related cardiovascular diseases, NHC Key Laboratory of Cell Transplantation, Harbin Medical University & Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, China. FAU - Yang, Xu AU - Yang X AD - Departments of Pharmacy and Cardiology, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Heilongjiang key laboratory for Metabolic disorder & cancer related cardiovascular diseases, NHC Key Laboratory of Cell Transplantation, Harbin Medical University & Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, China. FAU - Yang, Yan-Chao AU - Yang YC AD - Departments of Pharmacy and Cardiology, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Heilongjiang key laboratory for Metabolic disorder & cancer related cardiovascular diseases, NHC Key Laboratory of Cell Transplantation, Harbin Medical University & Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, China. FAU - Dong, Bi-Han AU - Dong BH AD - Departments of Pharmacy and Cardiology, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Heilongjiang key laboratory for Metabolic disorder & cancer related cardiovascular diseases, NHC Key Laboratory of Cell Transplantation, Harbin Medical University & Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, China. FAU - Yao, Jie AU - Yao J AD - Departments of Pharmacy and Cardiology, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Heilongjiang key laboratory for Metabolic disorder & cancer related cardiovascular diseases, NHC Key Laboratory of Cell Transplantation, Harbin Medical University & Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, China. FAU - Yu, Chang-Jiang AU - Yu CJ AD - Departments of Pharmacy and Cardiology, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Heilongjiang key laboratory for Metabolic disorder & cancer related cardiovascular diseases, NHC Key Laboratory of Cell Transplantation, Harbin Medical University & Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, China. FAU - Lou, Jie AU - Lou J AD - Departments of Pharmacy and Cardiology, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Heilongjiang key laboratory for Metabolic disorder & cancer related cardiovascular diseases, NHC Key Laboratory of Cell Transplantation, Harbin Medical University & Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, China. FAU - Tang, Liang-Liang AU - Tang LL AD - Departments of Pharmacy and Cardiology, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Heilongjiang key laboratory for Metabolic disorder & cancer related cardiovascular diseases, NHC Key Laboratory of Cell Transplantation, Harbin Medical University & Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, China. FAU - Wu, Ming-Ming AU - Wu MM AD - Departments of Pharmacy and Cardiology, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Heilongjiang key laboratory for Metabolic disorder & cancer related cardiovascular diseases, NHC Key Laboratory of Cell Transplantation, Harbin Medical University & Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, China. FAU - Zhang, Zhi-Ren AU - Zhang ZR AD - Departments of Pharmacy and Cardiology, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Heilongjiang key laboratory for Metabolic disorder & cancer related cardiovascular diseases, NHC Key Laboratory of Cell Transplantation, Harbin Medical University & Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, China. FAU - Ma, He-Ping AU - Ma HP AD - Department of Physiology, Emory University School of Medicine, Atlanta, GA, United States. LA - eng GR - R01 DK100582/DK/NIDDK NIH HHS/United States PT - Journal Article DEP - 20210526 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 PMC - PMC8187945 OTO - NOTNLM OT - NaHS OT - cyclosporine A OT - epithelial sodium channel OT - hypertension OT - lovastatin COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2021/06/15 06:00 MHDA- 2021/06/15 06:01 PMCR- 2021/05/26 CRDT- 2021/06/14 09:35 PHST- 2021/02/07 00:00 [received] PHST- 2021/04/19 00:00 [accepted] PHST- 2021/06/14 09:35 [entrez] PHST- 2021/06/15 06:00 [pubmed] PHST- 2021/06/15 06:01 [medline] PHST- 2021/05/26 00:00 [pmc-release] AID - 665111 [pii] AID - 10.3389/fphar.2021.665111 [doi] PST - epublish SO - Front Pharmacol. 2021 May 26;12:665111. doi: 10.3389/fphar.2021.665111. eCollection 2021.