title: Egr-1 deficiency protects from renal inflammation and fibrosis.
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.
  
  
  
  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.
authors.affiliation: Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China.|Division of Nephrology, Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan, Republic of China.|Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, Republic of China.
authors.forename: Li-Chun
authors.initials: LC
authors.lastname: Ho
authors.affiliation: Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan, Republic of China.
authors.forename: Junne-Ming
authors.initials: JM
authors.lastname: Sung
authors.affiliation: Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan, Republic of China.
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Shen
authors.affiliation: Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China.
authors.forename: Huei-Fen
authors.initials: HF
authors.lastname: Jheng
authors.affiliation: Department of Microbiology and Immunology, National Cheng Kung University, Tainan, Taiwan, Republic of China.
authors.forename: Shun-Hua
authors.initials: SH
authors.lastname: Chen
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Tainan, Taiwan, Republic of China.
authors.forename: Pei-Jane
authors.initials: PJ
authors.lastname: Tsai
authors.affiliation: Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China. yaustsai@mail.ncku.edu.tw.|Research Center of Clinical Medicine, National Cheng Kung University Hospital, Tainan, Taiwan, Republic of China. yaustsai@mail.ncku.edu.tw.
authors.forename: Yau-Sheng
authors.initials: YS
authors.lastname: Tsai
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D051766:Early Growth Response Protein 1 / Q000235:genetics* / Q000378:metabolism; D005355:Fibrosis; D055786:Gene Knockout Techniques; D006801:Humans; D007668:Kidney / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D009395:Nephritis, Interstitial / Q000276:immunology / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D016212:Transforming Growth Factor beta
keywords: Early growth response-1; NLRP3 inflammasome; Renal failure; Renal fibrosis; Renal inflammation