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Abstract: PO0628

Disruption of the H3K4 Methyltransferase MLL-1/Menin Complex Attenuates Renal Fibrosis Development by Inhibiting Epithelial-Mesenchymal Transition and Fibroblast Activation

Session Information

  • CKD Mechanisms - 2
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Zou, Jianan, Rnode Island Hospital, Brown University, Providence, Rhode Island, China
  • Zhuang, Shougang, Rnode Island Hospital, Brown University, Providence, Rhode Island, China

Group or Team Name

  • Rhode Island Hospital, Brown University
Background

The MLL-1/menin was disrupted by MI-503 and/or siRNA in a murine model of renal fibrosis induced by unilateral ureteral obstruction (UUO), cultured mouse proximal tubular cells and fibroblasts exposed to serum and transforming growth factor β1 (TGFβ1). Protein expression or activation was determined by immunofluorescent microscopy and immunoblot analysis.

Methods

The MLL-1/menin was disrupted by MI-503 and/or siRNA in a murine model of renal fibrosis induced by unilateral ureteral obstruction (UUO), cultured mouse proximal tubular cells and fibroblasts exposed to serum and transforming growth factor β1 (TGFβ1). Protein expression or activation was determined by immunofluorescent microscopy and immunoblot analysis.

Results

Injury to the kidney increased MLL1 and menin expression and H3K4 mono-methylation (H3K4me1) in renal tubular epithelial cells and fibroblasts. Administration of MI-503, a highly selective inhibitor of the MLL1/menin complex, attenuated renal fibrosis and expression of α-smooth muscle actin, fibronectin and collagen I. Treatment with MI-503, MLL1 siRNA or menin siRNA also inhibited TGFβ1 and serum-induced activation of epithelial-mesenchymal transition (EMT) in vitro. Moreover, UUO injury induced epithelial expression of phospho-histone 3 at Serine 10 and expression of profibrotic factors, TGFβ1 and connective tissue growth factor; and blocking the MLL1/menin complex with MI-503 inhibited these responses. Finally, MLL1 inhibition reduced expression of snail and twist, two transcription factors involved in the development of EMT and renal fibrosis and the expression of proliferating cell nuclear antigen, cyclin D1 and p27 in fibroblasts.
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Conclusion

Our data suggest that targeting disruption of the MLL1/menin complex can attenuate renal fibrosis through inhibition of EMT and fibroblast activation/proliferation.

Funding

  • NIDDK Support