DNA demethylase Tet2 suppresses cisplatin-induced acute kidney injury

Yinwu Bao,Yunjing Zhang,Weiqiang Lin,Xi Yao,Jianhua Mao,Xianghui Fu,Yuan Yuan,Junni Wang,Huanhuan Zhu,Xishao Xie,Mengqiu Bai,Ying Wang,Jianghua Chen,Yi Yang

doi:10.1038/s41420-021-00528-7

Abstract

Demethylase Tet2 plays a vital role in the immune response. Acute kidney injury (AKI) initiation and maintenance phases are marked by inflammatory responses and leukocyte recruitment in endothelial and tubular cell injury processes. However, the role of Tet2 in AKI is poorly defined. Our study determined the degree of renal tissue damage associated with Tet2 gene expression levels in a cisplatin-induced AKI mice model. Tet2-knockout (KO) mice with cisplatin treatment experienced severe tubular necrosis and dilatation, inflammation, and AKI markers’ expression levels than the wild-type mice. In addition, the administration of Tet2 plasmid protected Tet2-KO mice from cisplatin-induced nephrotoxicity, but not Tet2-catalytic-dead mutant. Tet2 KO was associated with a change in metabolic pathways like retinol, arachidonic acid, linolenic acid metabolism, and PPAR signaling pathway in the cisplatin-induced mice model. Tet2 expression is also downregulated in other AKI mice models and clinical samples. Thus, our results indicate that Tet2 has a renal protective effect during AKI by regulating metabolic and inflammatory responses through the PPAR signaling pathway.

Highlights

Acute kidney injury (AKI) is a global public health concern impacting ∼13.3 million patients per year [1]
Tet2 is highly expressed in mice kidney, kidney cell line and decreased in cisplatin-induced AKI We first explored the in vitro and in vivo expression of the Tet2 gene under healthy and disease conditions
Quantitative PCR results showed a high expression of Tet2 mRNA in WT-mice kidney compared to Tet1 and Tet3 genes (Fig. 1B)

Summary

Introduction

Acute kidney injury (AKI) is a global public health concern impacting ∼13.3 million patients per year [1]. High concentration of cisplatin accumulation has toxic effects in the proximal tubule segment [4]. Multiple mechanisms such as ferroptosis oxidative stress injury, dysfunction of autophagy, necrosis, and apoptosis contribute to the pathogenesis of cisplatin-induced AKI, more and more evidence suggests inflammation to play a crucial role [5,6,7,8,9]. Cisplatin-induced AKI demonstrated an increased concentration of various proinflammatory cytokines such as IL-1β, IL-6, IL-18, tumor necrosis factor (TNF)-α, monocyte chemotactic protein-1 (MCP-1), and transforming growth factor-β1 (TGF-β1) [3, 10, 11]

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Results