NF-κB and TGFβ play critical roles in renal inflammation and fibrosis, and their regulation in the kidney is thus of great interest. Early growth response-1 (Egr-1), a transcription factor belonging to the immediate early gene family, has been found to regulate inflammation and fibrosis in non-kidney tissues, but its role in renal failure has not been clear. In this study, wild-type and Egr1 −/− mice were fed with an adenine-enriched diet to induce tubulointerstitial nephritis (TIN), and primary tubular epithelial cells (PTECs) were treated with pro-inflammatory and pro-fibrotic cytokines. Kidney tissues from patients with or without renal failure were stained for Egr-1. Our results showed that Egr-1 expression was upregulated in the kidney with TIN, and the tubular epithelial cell is the primary site for Egr-1 upregulation and nuclear translocation. Egr1 −/− mice were protected from renal failure, reflected by low levels of serum urea and creatinine. The protective effect was related to an attenuation of tubular injury, immune cell infiltration, NF-κB activity, and cytokine/chemokine expressions in the kidney. Renal fibrotic area and TGFβ signaling were also reduced in Egr1 −/− mice. In vitro study showed that Egr-1 deficiency attenuated the ordinary responses of PTECs to TNFα and TGFβ. Importantly, Egr-1 is of clinical significance since the activity of Egr-1 in renal tubular cells was upregulated in renal failure patients. Our study highlights the integrative role of Egr-1 in renal inflammation and fibrosis. Thus, Egr-1 may serve as a therapeutic target for human kidney diseases.
Renal failure activates Egr-1 in human and mouse tubular cells.
Egr-1 deficiency attenuates NF-κB and TGFβ-mediated renal inflammation/fibrosis.
Egr1 −/− PTECs respond weakly to pro-inflammatory or pro-fibrotic stimulation.
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We are grateful for the support from Human Biobank, Research Center of Clinical Medicine, National Cheng Kung University Hospital. We thank Dr. Ming-Jer Tang and his laboratory for providing the protocol and instructions for the primary culture of mouse proximal tubular cells. This study is supported by the research grants of NCKUEDA10201 and NCKUEDA10301 from E-Da Hospital and National Cheng Kung University Hospital, and the research grants of NHRI-EX104-10231SI from National Health Research Institute. It is also a part of the National Cheng Kung University Top-Notch Project.
The study was conducted according to the study protocol approved by the Institutional Review Board of National Cheng Kung University Hospital (permit number: B-ER-101-008). All Procedures for handling animals were done in accordance to ethical statements approved by the Institutional Animal Care and Use Committee of National Cheng Kung University.
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The authors declare that they have no conflict of interests.
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Ho, LC., Sung, JM., Shen, YT. et al. Egr-1 deficiency protects from renal inflammation and fibrosis. J Mol Med 94, 933–942 (2016). https://doi.org/10.1007/s00109-016-1403-6
- Early growth response-1
- Renal inflammation
- Renal fibrosis
- Renal failure
- NLRP3 inflammasome