PIEZO1 as a new target for hyperglycemic stress-induced neuropathic injury: The potential therapeutic role of bezafibrate

Hailin Liu; Lian Zhou; Xifeng Wang; Yue Lin; Pengcheng Yi; Yanhong Xiong; Fenfang Zhan; Lanqian Zhou; Yao Dong; Jun Ying; Lidong Wu; Guohai Xu; Fuzhou Hua

Biomedicine & Pharmacotherapy (Jul 2024)

PIEZO1 as a new target for hyperglycemic stress-induced neuropathic injury: The potential therapeutic role of bezafibrate

Hailin Liu,
Lian Zhou,
Xifeng Wang,
Yue Lin,
Pengcheng Yi,
Yanhong Xiong,
Fenfang Zhan,
Lanqian Zhou,
Yao Dong,
Jun Ying,
Lidong Wu,
Guohai Xu,
Fuzhou Hua

Affiliations

Hailin Liu: Department of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Key Laboratory of Anesthesiology of Jiangxi Province, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Province Key Laboratory of Molecular Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Department of Emergency, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
Lian Zhou: Key Laboratory of Anesthesiology of Jiangxi Province, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Department of Anesthesiology, Ganjiang New Area Hospital of the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
Xifeng Wang: Key Laboratory of Anesthesiology of Jiangxi Province, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Department of Anesthesiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
Yue Lin: Department of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Key Laboratory of Anesthesiology of Jiangxi Province, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
Pengcheng Yi: Department of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Key Laboratory of Anesthesiology of Jiangxi Province, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Province Key Laboratory of Molecular Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
Yanhong Xiong: Department of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Key Laboratory of Anesthesiology of Jiangxi Province, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Province Key Laboratory of Molecular Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
Fenfang Zhan: Department of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Key Laboratory of Anesthesiology of Jiangxi Province, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Province Key Laboratory of Molecular Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
Lanqian Zhou: Department of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Key Laboratory of Anesthesiology of Jiangxi Province, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Province Key Laboratory of Molecular Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
Yao Dong: Department of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Key Laboratory of Anesthesiology of Jiangxi Province, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Province Key Laboratory of Molecular Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
Jun Ying: Department of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Key Laboratory of Anesthesiology of Jiangxi Province, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
Lidong Wu: Key Laboratory of Anesthesiology of Jiangxi Province, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Department of Emergency, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
Guohai Xu: Department of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Key Laboratory of Anesthesiology of Jiangxi Province, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Corresponding authors at: Department of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
Fuzhou Hua: Department of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Key Laboratory of Anesthesiology of Jiangxi Province, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Corresponding authors at: Department of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.

Journal volume & issue: Vol. 176
p. 116837

Abstract

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Hyperglycemic stress can directly lead to neuronal damage. The mechanosensitive ion channel PIEZO1 can be activated in response to hyperglycemia, but its role in hyperglycemic neurotoxicity is unclear. The role of PIEZO1 in hyperglycemic neurotoxicity was explored by constructing a hyperglycemic mouse model and a high-glucose HT22 cell model. The results showed that PIEZO1 was significantly upregulated in response to high glucose stress. In vitro experiments have shown that high glucose stress induces changes in neuronal cell morphology and membrane tension, a key mechanism for PIEZO1 activation. In addition, high glucose stress upregulates serum/glucocorticoid-regulated kinase-1 (SGK1) and activates PIEZO1 through the Ca2+ pool and store-operated calcium entry (SOCE). PIEZO1-mediated Ca2+ influx further enhances SGK1 and SOCE, inducing intracellular Ca2+ peaks in neurons. PIEZO1 mediated intracellular Ca2+ elevation leads to calcium/calmodulin-dependent protein kinase 2α (CaMK2α) overactivation, which promotes oxidative stress and apoptosis signalling through p-CaMK2α/ERK/CREB and ox-CaMK2α/MAPK p38/NFκB p65 pathways, subsequently inducing synaptic damage and cognitive impairment in mice. The intron miR-107 of pantothenic kinase 1 (PANK1) is highly expressed in the brain and has been found to target PIEZO1 and SGK1. The PANK1 receptor is activated by peroxisome proliferator-activated receptor α (PPARα), an activator known to upregulate miR-107 levels in the brain. The clinically used lipid-lowering drug bezafibrate, a known PPARα activator, may upregulate miR-107 through the PPARɑ/PANK1 pathway, thereby inhibiting PIEZO1 and improving hyperglycemia-induced neuronal cell damage. This study provides a new idea for the pathogenesis and drug treatment of hyperglycemic neurotoxicity and diabetes-related cognitive dysfunction.

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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