Over-activation of TRPM2 ion channel accelerates blood-spinal cord barrier destruction in diabetes combined with spinal cord injury rat

Zhang, Susu; Zhao, Jiaxin; Wu, Man; Zhou, Yongxiu; Wu, Xuejuan; Du, Anyu; Tao, Yibing; Huang, Shanshan; Cai, Shufang; Zhou, Mei; Wei, Tao; Zhang, Yanren; Xie, Ling; Wu, Yanqing; Xiao, Jian

doi:10.7150/ijbs.80672

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Int J Biol Sci 2023; 19(8):2475-2494. doi:10.7150/ijbs.80672 This issue Cite

Research Paper

Over-activation of TRPM2 ion channel accelerates blood-spinal cord barrier destruction in diabetes combined with spinal cord injury rat

Susu Zhang^1#, Jiaxin Zhao^1#, Man Wu^1#, Yongxiu Zhou¹, Xuejuan Wu¹, Anyu Du¹, Yibing Tao¹, Shanshan Huang¹, Shufang Cai², Mei Zhou², Tao Wei², Yanren Zhang², Ling Xie¹, Yanqing Wu^2✉, Jian Xiao^1✉

1. Department of Wound Healing, The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.
2. The Institute of Life Sciences, Engineering Laboratory of Zhejiang Province for Pharmaceutical Development of Growth Factors, Wenzhou University, Wenzhou, 325035, China.
^# These authors contribute equally to this work.

Citation:

Zhang S, Zhao J, Wu M, Zhou Y, Wu X, Du A, Tao Y, Huang S, Cai S, Zhou M, Wei T, Zhang Y, Xie L, Wu Y, Xiao J. Over-activation of TRPM2 ion channel accelerates blood-spinal cord barrier destruction in diabetes combined with spinal cord injury rat. Int J Biol Sci 2023; 19(8):2475-2494. doi:10.7150/ijbs.80672. https://www.ijbs.com/v19p2475.htm

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Abstract

Spinal cord injury (SCI) is a devastating neurological disorder that often results in loss of motor and sensory function. Diabetes facilitates the blood-spinal cord barrier (BSCB) destruction and aggravates SCI recovery. However, the molecular mechanism underlying it is still unclear. Our study has focused on transient receptor potential melastatin 2 (TRPM2) channel and investigated its regulatory role on integrity and function of BSCB in diabetes combined with SCI rat. We have confirmed that diabetes is obviously not conductive to SCI recovery through accelerates BSCB destruction. Endothelial cells (ECs) are the important component of BSCB. It was observed that diabetes significantly worsens mitochondrial dysfunction and triggers excessive apoptosis of ECs in spinal cord from SCI rat. Moreover, diabetes impeded neovascularization in spinal cord from SCI rat with decreases of VEGF and ANG1. TRPM2 acts as a cellular sensor of ROS. Our mechanistic studies showed that diabetes significantly induces elevated ROS level to activate TRPM2 ion channel of ECs. Then, TRPM2 channel mediated the Ca²⁺ influx and subsequently activated p-CaMKII/eNOS pathway, and which in turn triggered the ROS production. Consequently, over-activation of TRPM2 ion channel results in excessive apoptosis and weaker angiogenesis during SCI recovery. Inhibition of TRPM2 with 2-Aminoethyl diphenylborinate (2-APB) or TRPM2 siRNA will ameliorate the apoptosis of ECs and promote angiogenesis, subsequently enhance BSCB integrity and improve the locomotor function recovery of diabetes combined with SCI rat. In conclusion, TRPM2 channel may be a key target for the treatment of diabetes combined with SCI rat.

Keywords: Spinal cord injury (SCI), Diabetes, Endothelial cells (ECs), Transient receptor potential melastatin 2 (TRPM2), Reactive oxygen species (ROS)

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APA

Zhang, S., Zhao, J., Wu, M., Zhou, Y., Wu, X., Du, A., Tao, Y., Huang, S., Cai, S., Zhou, M., Wei, T., Zhang, Y., Xie, L., Wu, Y., Xiao, J. (2023). Over-activation of TRPM2 ion channel accelerates blood-spinal cord barrier destruction in diabetes combined with spinal cord injury rat. International Journal of Biological Sciences, 19(8), 2475-2494. https://doi.org/10.7150/ijbs.80672.

ACS

Zhang, S.; Zhao, J.; Wu, M.; Zhou, Y.; Wu, X.; Du, A.; Tao, Y.; Huang, S.; Cai, S.; Zhou, M.; Wei, T.; Zhang, Y.; Xie, L.; Wu, Y.; Xiao, J. Over-activation of TRPM2 ion channel accelerates blood-spinal cord barrier destruction in diabetes combined with spinal cord injury rat. Int. J. Biol. Sci. 2023, 19 (8), 2475-2494. DOI: 10.7150/ijbs.80672.

NLM

CSE

Zhang S, Zhao J, Wu M, Zhou Y, Wu X, Du A, Tao Y, Huang S, Cai S, Zhou M, Wei T, Zhang Y, Xie L, Wu Y, Xiao J. 2023. Over-activation of TRPM2 ion channel accelerates blood-spinal cord barrier destruction in diabetes combined with spinal cord injury rat. Int J Biol Sci. 19(8):2475-2494.

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