Hydrogen Sulfide Inhibits High Glucose-Induced Neuronal Senescence by Improving Autophagic Flux via Up-regulation of SIRT1.

Lei Wu,Xuan Kang,Xiao-Qing Tang,Yu-Rong Xie,Hong-Lin Huang,Ying Chen,Chun-Yan Wang,Xiang Li,Yi-Yun Tang

doi:10.3389/fnmol.2019.00194

Abstract

Hyperglycemia, a key characteristic and risk factor for diabetes mellitus (DM), causes neuronal senescence. Hydrogen sulfide (H2S) is a novel neuroprotectant. The present work was to investigate the potential effect of H2S on hyperglycemia-induced neuronal senescence and the underlying mechanisms. We found that NaHS, a donor of H2S, inhibited high glucose (HG)-induced cellular senescence in HT22 cells (an immortalized mouse hippocampal cell line), as evidenced by a decrease in the number of senescence associated-β-galactosidase (SA-β-gal) positive cells, increase in the growth of cells, and down-regulations of senescence mark proteins, p16INK4a and p21CIP1. NaHS improved the autophagic flux, which is judged by a decrease in the amount of intracellular autophagosome as well as up-regulations of LC3II/I and P62 in HG-exposed HT22 cells. Furthermore, blocked autophagic flux by chloroquine (CQ) significantly abolished NaHS-exerted improvement in the autophagic flux and suppression in the cellular senescence of GH-exposed HT22 cells, which indicated that H2S antagonizes HG-induced neuronal senescence by promoting autophagic flux. We also found that NaHS up-regulated the expression of silent mating type information regulation 2 homolog 1 (SIRT1), an important anti-aging protein, in HG-exposed HT22 cells. Furthermore, inhibition of SIRT1 by sirtinol reversed the protection of H2S against HG-induced autophagic flux blockade and cellular senescence in HT22 cells. These data indicated that H2S protects HT22 cells against HG-induced neuronal senescence by improving autophagic flux via up-regulation of SIRT1, suggesting H2S as a potential treatment strategy for hyperglycemia-induced neuronal senescence and neurotoxicity.

Highlights

Diabetes mellitus (DM) increases the risk of central nervous system disease leading to encephalopathy (Sima et al, 2004), because hyperglycemia, the mainly characterized of DM, triggers neuronal damage (Fan et al, 2016; Kumar et al, 2017)
We investigated the effect of H2S on high glucose (HG)-induced cellular senescence in HT22 cells
The main findings of the present study are as followings: (1) NaHS inhibits HG-induced cellular senescence of HT22 cells; (2) NaHS restores HG-induced autophagic flux dysfunction in HT22 cells; (3) inhibition of autophagic flux by CQ reversed H2S-restored autophagic flux in HG-exposed HT22 cells; (4) CQ abolishes the protective effects of H2S on HG-induced cellular senescence in HT22 cells; (5) H2S upregulates the expression of SIRT1 protein in HG-exposed HT22 cells; and (6) sirtinol, an inhibitor of SIRT1, reverses the improvement of H2S in HG-induced autophagic flux disturbance in HT22 cells and blocks the protection of H2S against HG-induced cellular senescence in HT22 cells

Summary

Introduction

Diabetes mellitus (DM) increases the risk of central nervous system disease leading to encephalopathy (Sima et al, 2004), because hyperglycemia, the mainly characterized of DM, triggers neuronal damage (Fan et al, 2016; Kumar et al, 2017). Increasing evidence demonstrated that hyperglycemia induces neuronal senescence (Reno et al, 2013; Kaur et al, 2017; Yerra et al, 2017; Zhang et al, 2019). Increasing the defenses against hyperglycemia-induced neuronal senescence represents a future strategy for diabetic encephalopathy. It has been confirmed that H2S protects neuronal cells against stress-induced senescence (Liu et al, 2013; Xie et al, 2014). We speculated that H2S protects neurons against hyperglycemia-induced cellular senescence

Methods

Results

Conclusion