Inhibition the ubiquitination of ENaC and Na,K-ATPase with erythropoietin promotes alveolar fluid clearance in sepsis-induced acute respiratory distress syndrome

Ye Gao; Fei Cao; Xinyi Tian; Qianping Zhang; Congcong Xu; Bowen Ji; Ye-an Zhang; Linan Du; Jun Han; Li Li; Siyu Zhou; Yuqiang Gong; Binyu Ying; Fang Gao-Smith; Shengwei Jin

Biomedicine & Pharmacotherapy (May 2024)

Inhibition the ubiquitination of ENaC and Na,K-ATPase with erythropoietin promotes alveolar fluid clearance in sepsis-induced acute respiratory distress syndrome

Ye Gao,
Fei Cao,
Xinyi Tian,
Qianping Zhang,
Congcong Xu,
Bowen Ji,
Ye-an Zhang,
Linan Du,
Jun Han,
Li Li,
Siyu Zhou,
Yuqiang Gong,
Binyu Ying,
Fang Gao-Smith,
Shengwei Jin

Affiliations

Ye Gao: Department of Anaesthesia, Pain and Critical Care, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Zhejiang, China; Laboratory of Anesthesiology of Zhejiang Province, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China
Fei Cao: Department of Anaesthesia, Pain and Critical Care, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Zhejiang, China; Laboratory of Anesthesiology of Zhejiang Province, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China; Department of Anesthesiology, Sun Yat-sen University Cancer Center, Guangzhou, China
Xinyi Tian: Department of Anaesthesia, Pain and Critical Care, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Zhejiang, China; Laboratory of Anesthesiology of Zhejiang Province, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China
Qianping Zhang: Department of Anaesthesia, Pain and Critical Care, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
Congcong Xu: Department of Anaesthesia, Pain and Critical Care, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Zhejiang, China; Laboratory of Anesthesiology of Zhejiang Province, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China
Bowen Ji: Department of Anaesthesia, Pain and Critical Care, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Zhejiang, China; Laboratory of Anesthesiology of Zhejiang Province, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China
Ye-an Zhang: Department of Anaesthesia, Pain and Critical Care, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Zhejiang, China; Laboratory of Anesthesiology of Zhejiang Province, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China
Linan Du: Department of Anaesthesia, Pain and Critical Care, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Zhejiang, China; Laboratory of Anesthesiology of Zhejiang Province, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China
Jun Han: Department of Anaesthesia, Pain and Critical Care, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Zhejiang, China; Laboratory of Anesthesiology of Zhejiang Province, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China
Li Li: Department of Anaesthesia, Pain and Critical Care, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Zhejiang, China; Laboratory of Anesthesiology of Zhejiang Province, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China
Siyu Zhou: Department of Anaesthesia, Pain and Critical Care, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Zhejiang, China; Laboratory of Anesthesiology of Zhejiang Province, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China
Yuqiang Gong: Department of Anaesthesia, Pain and Critical Care, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Zhejiang, China; Laboratory of Anesthesiology of Zhejiang Province, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China
Binyu Ying: Department of Anaesthesia, Pain and Critical Care, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Zhejiang, China; Laboratory of Anesthesiology of Zhejiang Province, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China
Fang Gao-Smith: Department of Anaesthesia, Pain and Critical Care, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Zhejiang, China; Laboratory of Anesthesiology of Zhejiang Province, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China; Centre for Translational Inflammation Research, Institute of Inflammation and Aging, University of Birmingham, Birmingham, United Kingdom; Correspondence to: Department of Anaesthesia and Critical Care, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Shengwei Jin: Department of Anaesthesia, Pain and Critical Care, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Zhejiang, China; Laboratory of Anesthesiology of Zhejiang Province, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Zhejiang, China; Correspondence to: Department of Anaesthesia and Critical Care, the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.

Journal volume & issue: Vol. 174
p. 116447

Abstract

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Sepsis-induced acute respiratory distress syndrome (ARDS) causes significant fatalities worldwide and lacks pharmacological intervention. Alveolar fluid clearance (AFC) plays a pivotal role in the remission of ARDS and is markedly impaired in the pathogenesis of ARDS. Here, we demonstrated that erythropoietin could effectively ameliorate lung injury manifestations and lethality, restore lung function and promote AFC in a rat model of lipopolysaccharide (LPS)-induced ARDS. Moreover, it was proven that EPO-induced restoration of AFC occurs through triggering the total protein expression of ENaC and Na,K-ATPase channels, enhancing their protein abundance in the membrane, and suppressing their ubiquitination for degeneration. Mechanistically, the data indicated the possible involvement of EPOR/JAK2/STAT3/SGK1/Nedd4–2 signaling in this process, and the pharmacological inhibition of the pathway markedly eliminated the stimulating effects of EPO on ENaC and Na,K-ATPase, and subsequently reversed the augmentation of AFC by EPO. Consistently, in vitro studies of alveolar epithelial cells paralleled with that EPO upregulated the expression of ENaC and Na,K-ATPase, and patch-clamp studies further demonstrated that EPO substantially strengthened sodium ion currents. Collectively, EPO could effectively promote AFC by improving ENaC and Na,K-ATPase protein expression and abundance in the membrane, dependent on inhibition of ENaC and Na,K-ATPase ubiquitination, and resulting in diminishing LPS-associated lung injuries.

Published in Biomedicine & Pharmacotherapy

ISSN: 0753-3322 (Print); 1950-6007 (Online)
Publisher: Elsevier
Country of publisher: France
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.journals.elsevier.com/biomedicine-and-pharmacotherapy

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