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IRF-1 promotes renal fibrosis by downregulation of Klotho

Yan Li1, Yong Liu1, Yinghui Huang1

  • 1Department of Nephrology, The Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Kidney Center of PLA, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|January 23, 2020
PubMed

Insights

Interferon regulatory factor 1 (IRF-1) drives kidney fibrosis by reducing Klotho. Suppressing IRF-1 may offer a new therapeutic strategy for chronic kidney disease (CKD).

Area of Science:

  • Nephrology
  • Molecular Biology
  • Pathology

Background:

  • Renal fibrosis is a key driver of chronic kidney disease (CKD) progression.
  • The precise molecular mechanisms underlying renal fibrosis remain incompletely understood.
  • Interferon regulatory factor 1 (IRF-1) has been identified as a potential factor in kidney disease.

Purpose of the Study:

  • To investigate the role of IRF-1 in the pathogenesis of renal fibrosis.
  • To elucidate the molecular mechanisms by which IRF-1 influences renal fibrosis.
  • To explore IRF-1 as a potential therapeutic target for CKD.

Main Methods:

  • Analysis of IRF-1 expression in kidney tissues from CKD patients and mouse models (unilateral ureteral obstruction and Adriamycin nephropathy).
  • In vitro studies using tubular epithelial cells to assess the effects of IRF-1 overexpression on profibrotic markers and Klotho expression.
  • Luciferase reporter assays and ChIP assays to determine the transcriptional regulation of Klotho by IRF-1 and C/EBP-β.
  • Investigating the role of tumor necrosis factor-alpha in IRF-1 induction and the effect of IRF-1 deletion on renal fibrosis in a mouse model.

Main Results:

  • IRF-1 expression was significantly elevated in fibrotic kidneys of CKD patients and mouse models.
  • Overexpression of IRF-1 in tubular epithelial cells induced profibrotic markers and downregulated Klotho.
  • IRF-1 repressed Klotho transcription by downregulating C/EBP-β, which directly binds to the Klotho promoter.
  • Tumor necrosis factor-alpha was identified as a potential inducer of IRF-1 in tubular epithelial cells.
  • Genetic deletion of IRF-1 attenuated renal fibrosis in unilateral ureteral obstruction mice.

Conclusions:

  • IRF-1 plays a significant role in the pathogenesis of renal fibrosis by downregulating Klotho expression.
  • The IRF-1/C/EBP-β pathway is a key regulator of Klotho transcription in the context of kidney fibrosis.
  • Targeting IRF-1 represents a promising therapeutic strategy for mitigating renal fibrosis in CKD.
Keywords:
IRFKlothoTNF-αchronic kidney diseaserenal fibrosis

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