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Kidney Week

Abstract: TH-PO506

The Transcription Factor STAT3 Plays Key Roles in the Development of Kidney Fibrosis by Increasing Proliferation and Differentiation of Pericytes into Myofibroblasts

Session Information

  • CKD: Mechanisms - I
    November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Ajay, Amrendra Kumar, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Zhao, Li, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Jadhav, Shreyas, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Ding, Yan, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Hsiao, Li-Li, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Bonventre, Joseph V., Brigham and Women's Hospital, Boston, Massachusetts, United States

Group or Team Name

  • Kidney Innovation Centre
Background

STAT3 is a key transcription factor, which plays important roles in inflammatory diseases. STAT3 has been shown to transcribe genes important for the acute and chronic phase of various malignant. There is little information regarding the function of STAT3 in stromal cells.

Methods

Phosphorylation of STAT3 was evaluated in 5 patient biopsy samples using immunofluorescence. In mice, stromal cell-specific STAT3 deletion was performed by breeding STAT3 floxed mice with FoxD1 Cre mice. Kidney fibrosis was induced by administering 300 mg/kg folic acid (FA) or 5 mg/kg body weight aristolochic acid (AA). Cell migration was evaluated with wound scratch assays. RT-PCR, immunostaining and western blotting were performed to measure changes in STAT3-dependent genes and to quantitate pro-fibrotic cytokines.

Results

STAT3 phosphorylation was increased in tubular epithelial cells and interstitial cells of 5 human subjects with chronic kidney disease. Deletion of STAT3 from stromal cells protects mice from FA or AA-induced kidney fibrosis at 7- and 14-days post-treatment respectively. Fibrotic markers, including fibronectin, collagen1a1, and α-SMA were reduced in STAT3 KO mice. STAT3 KO mice show similar acute injury {shown by histopathology and mRNA levels of TNFa and KIM-1 (Kidney Injury Molecule-1, acute kidney injury marker)}. KIM-1 expression was decreased at 7 and 14 days in STAT3 KO mice. In human primary pericytes in vitro, STAT3 was phosphorylated after treatment with IL-6 or Colivelin (a small peptide activator of STAT3). Inhibition of IL-6-induced STAT3 phosphorylation significantly decreased the proliferation, production of profibrotic cytokines and differentiation of pericytes into myofibroblasts.

Conclusion

STAT3 plays key roles in the development of kidney fibrosis by increasing proliferation and differentiation of pericytes into myofibroblasts. Thus, STAT3 may be a potential therapeutic target for kidney fibrosis.

Funding

  • Private Foundation Support