Hyperglycemic stress induces oxidative damage of enteric glial cells by triggering redoxosomes/p66SHC activation

ABSTRACT

Objectives

Diabetic gastrointestinal dysfunction (DGD) is a serious complication of diabetic mellitus (DM), affecting the enteric nervous system (ENS), particular enteric glial cells (EGCs). This study aimed to elucidate the effects and underlying molecular mechanisms of hyperglycemic stress on EGCs in in vitro and in vivo models of DM.

Methods

In in vitro studies, enteric glial cell line CRL-2690 was exposed to hyperglycemia stress, and cell viability, cell apoptosis and oxidative damage were assessed. In in vivo studies, STZ-induced diabetic mice were constructed, and cell apoptosis and oxidative damage of EGCs in the duodenum of DM mice were assessed.

Results

The results showed that hyperglycemic stress markedly induced oxidative damage of EGCs in in vitro and in vivo models of DM. This damage was found to be dependent on the activation of redoxosomes, which involved the phosphorylation of SRC and Vav2, the up-regulation of active RAC1-GTP, and the activation of NADPH oxidase (NOX). Moreover, inhibitors of redoxosomes, such as the RAC1 inhibitor NSC23766 and the NOX inhibitor VAS2870, effectively mitigated the hyperglycemic stress-induced oxidative damage of EGCs. Additionally, inhibition of p66SHC, a downstream target of redoxosomes, attenuated oxidative damage of EGCs under hyperglycemic stress.

Discussion

Our findings suggest that the redoxosomes/p66SHC signaling is involved in the oxidative damage of EGCs during the pathological process of DGD. This signaling cascade may represent a potential therapeutic target for the treatment of DGD.

KEYWORDS:

• Diabetic gastrointestinal dysfunction
• enteric glial cells
• hyperglycemic stress
• redoxosomes/p66SHC signaling

Acknowledgements

We sincerely appreciate the help of the member of The First Affiliated Hospital of Nanjing Medical University, The Affiliated Wuxi People's Hospital of Nanjing Medical University and the Jiangsu Institute of Nuclear Medicine.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The authors confirm that the datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Ethical approval

All protocols used for animal manipulation were approved by the Institutional Animal Care Committee.

Additional information

Funding

This work was supported by National Natural Science Foundation of China [grant number 82070832], Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions. Cohort and Clinical Research Program of Wuxi Medical Center, Nanjing Medical University [grant number WMCC202308, WMCC202322], Major Project of Wuxi Commission of Health (Z202110), Project of Jiangsu Administration of Traditional Chinese Medicine [grant number MS2022145, MS2023166], the Research Project Fund from Wuxi Municipal Health Commission [grant number M202011] and Wuxi Science and Technology Development Fund [grant number N20202006].