Histone Methylation Inhibitor DZNep Ameliorated the Renal Ischemia-Reperfusion Injury via Inhibiting TIM-1 Mediated T Cell Activation

Jiawei Li,Ruiming Rong,Jiyan Wang,Yi Zhang,Yin Celeste Cheuk,Jina Wang,Yichen Jia,Yue Qiu,Ruirui Sang,Long Li

doi:10.3389/fmed.2020.00305

Abstract

Renal ischemia-reperfusion injury (IRI) after renal transplantation often leads to the loss of kidney graft function. However, there is still a lack of efficient regimens to prevent or alleviate renal IRI. Our study focused on the renoprotective effect of 3-Deazaneplanocin A (DZNep), which is a histone methylation inhibitor. We found that DZNep significantly alleviated renal IRI by suppressing nuclear factor kappa-B (NF-κB), thus inhibiting the expression of inflammatory factors in renal tubular epithelial cells in vivo or in vitro. After treatment with DZNep, T cell activation was impaired in the spleen and kidney, which correlated with the downregulated expression of T-cell immunoglobulin mucin (TIM)-1 on T cells and TIM-4 in macrophages. In addition, pretreatment with DZNep was not sufficient to protect the kidney, while administration of DZNep from before to after surgery significantly ameliorated IRI. Our findings suggest that DZNep can be a novel strategy for preventing renal IRI following kidney transplantation.

Highlights

Ischemia-reperfusion injury (IRI) is the leading cause of renal function impairment after renal transplantation
We demonstrated that Deazaneplanocin A (DZNep) treatment can alleviate renal IRI in mice by inhibiting T cell activation through direct and indirect pathways
Mice were randomly divided into six groups (n = 6) according to the different treatments: [1] sham group; [2] DZNep group (DZNep treated without renal pedicle occlusion); [3] IRI group; [4] IRI+DZNep pretreatment group; [5] IRI+DZNep posttreatment group; [6] IRI+DZNep group

Summary

INTRODUCTION

Ischemia-reperfusion injury (IRI) is the leading cause of renal function impairment after renal transplantation. T cells mediate IRI or rejection, impair the recovery of kidney grafts, and even induce renal interstitial fibrosis. Inhibiting the activation of T cells has the potential to promote the functional recovery of kidney grafts. Recent research has broadened its potential therapeutic effects in ischemic brain injury by promoting microglial activation [18] and tubulointerstitial fibrosis by inhibiting the expression of fibrogenic genes. It has become an ideal medication for epigenetic therapy owing to its reversible effects on gene expression. We demonstrated that DZNep treatment can alleviate renal IRI in mice by inhibiting T cell activation through direct and indirect pathways. Our findings suggest that DZNep can be a novel strategy for preventing renal IRI following kidney transplantation

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