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STAT4-Mediated Klotho Up-Regulation Contributes to the Brain Ischemic Tolerance by Cerebral Ischemic Preconditioning via Inhibiting Neuronal Pyroptosis

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Abstract

Our previous study has proved that the Klotho up-regulation participated in cerebral ischemic preconditioning (CIP)-induced brain ischemic tolerance. However, the exact neuroprotective mechanism of Klotho in CIP remains unclear. We explored the hypothesis that STAT4-mediated Klotho up-regulation contributes to the CIP-induced brain ischemic tolerance via inhibiting neuronal pyroptosis. Firstly, the expressions of pyroptosis-associated proteins (i.e., NLRP3, GSDMD, pro-caspase-1, and cleaved caspase-1) in hippocampal CA1 region were determined during the process of brain ischemic tolerance. We found the expression of pyroptosis-associated proteins was significantly up-regulated in the ischemic insult (II) group, and showed no significant changes in the CIP group. The expression level of each pyroptosis-associated proteins was lower in the CIP + II group than that in the II group. Inhibition of Klotho expression increased the expression of pyroptosis-associated proteins in the CIP + II group and blocked the CIP-induced brain ischemic tolerance. Injection of Klotho protein decreased the expression of pyroptosis-associated proteins in the II group, and protected neurons from ischemic injury. Secondly, the transcription factor STAT4 of Klotho was identified by bioinformatic analysis. Double luciferase reporter gene assay and chromatin immunoprecipitation assay showed STAT4 can bind to the site between nt − 881 and – 868 on the Klotho promoter region and positively regulates Klotho expression. Moreover, we found CIP significantly enhanced the expression of STAT4. Knockdown STAT4 suppressed Klotho up-regulation after CIP and blocked the CIP-induced brain ischemic tolerance. Collectively, it can be concluded that STAT4-mediated the up-regulation of Klotho contributed to the brain ischemic tolerance induced by CIP via inhibiting pyroptosis.

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Data Availability

The data used in the present study are available from the corresponding author on reasonable request.

Abbreviations

AAV:

Adeno-associated virus

BCCAs:

Bilateral common carotid arteries

CIP:

Cerebral ischemic preconditioning

ND:

Neuronal density

DND:

Delayed neuronal death

d:

Day

GSDMD:

Gasdermin D

h:

Hour

II:

Ischemic insult

i.c.v. :

Intracerebroventricular

KL:

Klotho

min:

Minute

NC:

Negative control

NLRP3:

NOD-like receptor family pyrin domain containing 3

NS:

Statistically nonsignificant

STAT:

Signal transducer and activator of transcription

siRNA:

Small interfering RNA

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Acknowledgements

We thank Dr. Chenguang Zhao for her linguistic assistance during the preparation of this manuscript.

Funding

This work was supported by the Natural Science Foundation of Hebei Province (Nos. H2021206160 and H2022206579) and the National Natural Science Foundation of China (No. 81971228).

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  1. Xi-Yun Liu and Ling-Yan Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Pathophysiology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, Hebei, 050017, People’s Republic of China

    Xi-Yun Liu, Ling-Yan Zhang, Xiao-Yu Wang, Shi-chao Li, Yu-Yan Hu, Jing-Ge Zhang, Xiao-Hui Xian, Wen-Bin Li & Min Zhang

  2. Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Shijiazhuang, People’s Republic of China

    Ling-Yan Zhang, Yu-Yan Hu, Jing-Ge Zhang, Xiao-Hui Xian, Wen-Bin Li & Min Zhang

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Xi-Yun Liu and Ling-Yan Zhang performed experiments. Xi-Yun Liu, Shi-chao Li, and Xiao-Yu Wang analyzed data and drafted the manuscript. Yu-Yan Hu and Xiao-Hui Xian drafted the figures. Min Zhang, Jing-Ge Zhang, and Wen-Bin Li designed the study and contributed to editing the final draft. All authors read and approved the final manuscript.

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Liu, XY., Zhang, LY., Wang, XY. et al. STAT4-Mediated Klotho Up-Regulation Contributes to the Brain Ischemic Tolerance by Cerebral Ischemic Preconditioning via Inhibiting Neuronal Pyroptosis. Mol Neurobiol 61, 2336–2356 (2024). https://doi.org/10.1007/s12035-023-03703-2

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