TY - JOUR
T1 - Egr-1 deficiency protects from renal inflammation and fibrosis
AU - Ho, Li Chun
AU - Sung, Junne Ming
AU - Shen, Yi Ting
AU - Jheng, Huei Fen
AU - Chen, Shun Hua
AU - Tsai, Pei Jane
AU - Tsai, Yau Sheng
N1 - Publisher Copyright:
© 2016, Springer-Verlag Berlin Heidelberg.
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - Abstract: 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. Key messages: 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.
AB - Abstract: 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. Key messages: 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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U2 - 10.1007/s00109-016-1403-6
DO - 10.1007/s00109-016-1403-6
M3 - Article
C2 - 26960759
AN - SCOPUS:84960115749
VL - 94
SP - 933
EP - 942
JO - Journal of Molecular Medicine
JF - Journal of Molecular Medicine
SN - 0946-2716
IS - 8
ER -