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

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.

No safe renal warm ischemia time—The molecular network characteristics and pathological features of mild to severe ischemia reperfusion kidney injury

“…The experimental mouse models of renal ischemia/reperfusion injury (IRI) can well simulate renal injury caused by renal artery occlusion in human partial nephrectomy. However, there are various surgical methods for IRI model reported in different studies: bilateral IRI (bIRI) ( Chen et al, 2018 ; Chen et al, 2022 ), contralateral kidney reservation plus unilateral IRI (uIRI) ( Godwin et al, 2010 ; Huang et al, 2022 ), contralateral nephrectomy plus unilateral IRI (uIRIx) ( Ferhat et al, 2018 ; Wang et al, 2022 ), unilateral IRI plus contralateral resection 14d before surgery ( Chou et al, 2020 ), and so on ( Wei and Dong, 2012 ; Fu et al, 2018 ; Wei et al, 2019a ; Shiva et al, 2020 ). The setting of IRI ischemia time varies from 18min to 35min.…”

“…Among the 863 DEGs in the 16 min–0 min group, Kim1 (Havcr1) presented the highest expression DEGs, and the log(fold change) was 4.99. Since Kim1 can be detected in blood and urine ( Vinken et al, 2012 ), and its peak occurred 24 h after IRI ( Chen et al, 2022 ), blood or urine tests for Kim1 may be considered a possible method to detect signs of mild kidney damage”.…”

Activated SOX9+ renal epithelial cells promote kidney repair through secreting factors

“…Previous studies by our group and others 9,10,17,41 indicated activation of SOX9+ cells in injured rodent kidneys for tissue repair purposes, however whether a similar mechanism is applied to humans remained unknown. To investigate the existence of tissue resident SOX9+ populations, human kidney sc-RNA-seq datasets (GSE171458; GSE174220) obtained from two healthy controls (HC) and two patients with AKI were analysed.…”

Caspase 6/NR4A1/SOX9 signaling axis regulates hepatic inflammation and pyroptosis in ischemia-stressed fatty liver

“…Thus far, more than 20 SOX genes have been discovered in vertebrates, with SOX9 being the most extensively studied [ 15 ]. Previous study demonstrated that SOX9 attenuated acute kidney injury by regulating Wnt/β-catenin signaling [ 16 ]. In contrast, a Tomo-sequencing assay of ischemic myocardium identified collagen I-positive fibroblast-derived SOX9 as the key regulator of IR-induced myocardial fibrosis [ 17 ].…”