Knockdown of CLC-3 may improve cognitive impairment caused by diabetic encephalopathy.
CLC-3
Diabetic encephalopathy
Morris Water Maze test
Novel object recognition test
Journal
Diabetes research and clinical practice
ISSN: 1872-8227
Titre abrégé: Diabetes Res Clin Pract
Pays: Ireland
ID NLM: 8508335
Informations de publication
Date de publication:
Aug 2022
Aug 2022
Historique:
received:
01
02
2022
revised:
05
06
2022
accepted:
16
06
2022
pubmed:
7
7
2022
medline:
9
9
2022
entrez:
6
7
2022
Statut:
ppublish
Résumé
Diabetic encephalopathy(DE) is a neurological complication of diabetes, and its pathogenesis is unclear. Current studies indicate that insulin receptors and downstream signaling pathways play a key role in the occurrence and development of DE. Additionally, CLC-3, a member of the CLC family of anion channels and transporters, is closely related to the secretion and processing of insulin. Here, we investigated the changes and putative roles of CLC-3 in diabetic encephalopathy. To this aim, we combined lentivirus and adeno-associated virus gene transfer to change the expression level of CLC-3 in the HT-22 hippocampal cell line and hippocampal CA1. We studied the role of CLC-3 in DE through the Morris water maze test.CLC-3 expression increased significantly in HT-22 cells cultured with high glucose and STZ-induced DE model hippocampus. Moreover, Insulin receptor(IR) and downstream PI3K/AKT/GSK3β signaling pathways were also dysfunctional. After knocking down CLC-3, impaired cell proliferation, apoptosis, IR and the downstream PI3K/AKT/GSK3β signaling pathways were significantly improved. However, when CLC-3 was overexpressed, the neurotoxicity induced by high glucose was further aggravated. Rescue experiments found that through the use of inhibitors such as GSK3β, the PI3K/AKT/GSK3β signaling pathways pathway changes with the use of inhibition, and the expression of related downstream signaling molecules such as Tau and p-Tau also changes accordingly. Using adeno-associated virus gene transfer to knock down CLC-3 in the hippocampal CA1 of the DE model, the IR caused by DE and the dysfunction of the downstream PI3K/AKT/GSK3β signaling pathway were significantly improved. In addition, the impaired spatial recognition of DE was partially restored. Our study proposes that CLC-3, as a key molecule, may regulate insulin receptor signaling and downstream PI3K/AKT/GSK3β signaling pathways and affect the pathogenesis of diabetic encephalopathy.
Sections du résumé
BACKGROUND
BACKGROUND
Diabetic encephalopathy(DE) is a neurological complication of diabetes, and its pathogenesis is unclear. Current studies indicate that insulin receptors and downstream signaling pathways play a key role in the occurrence and development of DE. Additionally, CLC-3, a member of the CLC family of anion channels and transporters, is closely related to the secretion and processing of insulin. Here, we investigated the changes and putative roles of CLC-3 in diabetic encephalopathy.
RESULTS
RESULTS
To this aim, we combined lentivirus and adeno-associated virus gene transfer to change the expression level of CLC-3 in the HT-22 hippocampal cell line and hippocampal CA1. We studied the role of CLC-3 in DE through the Morris water maze test.CLC-3 expression increased significantly in HT-22 cells cultured with high glucose and STZ-induced DE model hippocampus. Moreover, Insulin receptor(IR) and downstream PI3K/AKT/GSK3β signaling pathways were also dysfunctional. After knocking down CLC-3, impaired cell proliferation, apoptosis, IR and the downstream PI3K/AKT/GSK3β signaling pathways were significantly improved. However, when CLC-3 was overexpressed, the neurotoxicity induced by high glucose was further aggravated. Rescue experiments found that through the use of inhibitors such as GSK3β, the PI3K/AKT/GSK3β signaling pathways pathway changes with the use of inhibition, and the expression of related downstream signaling molecules such as Tau and p-Tau also changes accordingly. Using adeno-associated virus gene transfer to knock down CLC-3 in the hippocampal CA1 of the DE model, the IR caused by DE and the dysfunction of the downstream PI3K/AKT/GSK3β signaling pathway were significantly improved. In addition, the impaired spatial recognition of DE was partially restored.
CONCLUSION
CONCLUSIONS
Our study proposes that CLC-3, as a key molecule, may regulate insulin receptor signaling and downstream PI3K/AKT/GSK3β signaling pathways and affect the pathogenesis of diabetic encephalopathy.
Identifiants
pubmed: 35792204
pii: S0168-8227(22)00784-7
doi: 10.1016/j.diabres.2022.109970
pii:
doi:
Substances chimiques
Chloride Channels
0
ClC-3 channel
0
Receptor, Insulin
EC 2.7.10.1
Glycogen Synthase Kinase 3 beta
EC 2.7.11.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
109970Informations de copyright
Copyright © 2022 Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.