Theranostics 2022; 12(12):5434-5450. doi:10.7150/thno.73426 This issue

Research Paper

Transient upregulation of EGR1 signaling enhances kidney repair by activating SOX9+ renal tubular cells

Jian-Wen Chen1#, Meng-Jie Huang1✉#, Xiao-Niao Chen1,2,3, Ling-Ling Wu1, Qing-Gang Li1, Quan Hong1, Jie Wu1, Fei Li1, Liang-Mei Chen1, Yu Dong1, Guang-Yan Cai1, Xue-Yuan Bai1, Zongjin Li4✉, Xiang-Mei Chen1✉

1. Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing 100853, China.
2. Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China.
3. Department of Ophthalmology, Chinese PLA General Hospital, Beijing 100853, China.
4. Nankai University School of Medicine, 94 Weijin Road, Tianjin, 300071, China.
#These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Chen JW, Huang MJ, Chen XN, Wu LL, Li QG, Hong Q, Wu J, Li F, Chen LM, Dong Y, Cai GY, Bai XY, Li Z, Chen XM. Transient upregulation of EGR1 signaling enhances kidney repair by activating SOX9+ renal tubular cells. Theranostics 2022; 12(12):5434-5450. doi:10.7150/thno.73426. Available from https://www.thno.org/v12p5434.htm

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Abstract

Graphic abstract

Background: Acute kidney injury (AKI) is associated with damage to the nephrons and tubular epithelial cells (TECs), which can lead to chronic kidney disease and end-stage renal disease. Identifying new biomarkers before kidney dysfunction will offer crucial insight into preventive and therapeutic options for the treatment of AKI. Early growth response 1 (EGR1) has been found to be a pioneer transcription factor that can sequentially turn on/off key downstream genes to regulate whole-body regeneration processes in the leopard worm. Whether EGR1 modulates renal regeneration processes in AKI remains to be elucidated.

Methods: AKI models of ischemia-reperfusion injury (IRI) and folic acid (FA) were developed to investigate the roles of EGR1 in kidney injury and regeneration. To further determine the function of EGR1, Egr1-/- mice were applied. Furthermore, RNA sequencing of renal TECs, Chromatin Immunoprecipitation (ChIP) assay, and Dual-luciferase reporter assay were carried out to investigate whether EGR1 affects the expression of SOX9.

Results: EGR1 is highly expressed in the kidney after AKI both in humans and mice through analysis of the Gene Expression Omnibus (GEO) database. Furthermore, we verified that EGR1 rapidly up-regulates in the very early stage of IRI and nephrotoxic models of AKI, and validation studies confirmed the essential roles of EGR1 in renal tubular cell regeneration. Further experiments affirmed that genetic inhibition of Egr1 aggravates the severity of AKI in mouse models. Furthermore, our results revealed that EGR1 could increase SOX9 expression in renal TECs by directly binding to the promoter of the Sox9 gene, thus promoting SOX9+ cell proliferation by activating the Wnt/β-catenin pathway.

Conclusions: Together, our results demonstrated that rapid and transient induction of EGR1 plays a renoprotective role in AKI, which highlights the prospects of using EGR1 as a potential therapeutic target for the treatment of AKI.

Keywords: Acute kidney injury (AKI), Early growth response 1 (EGR1), SOX9, Tubular epithelial cells (TECs), Regeneration