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Kidney Week

Abstract: PO0442

The MLL1/WDR5 Complex Contributes to Cisplatin-Induced Renal Epithelial Death by Promoting p53-mediated E-Cadherin Repression

Session Information

  • AKI: Novel Insights
    November 04, 2021 | Location: On-Demand, Virtual Only
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Zhang, Chunyun, Rhode Island Hospital, Providence, Rhode Island, United States
  • Guan, Yingjie Angie, Rhode Island Hospital, Providence, Rhode Island, United States
  • Bayliss, George P., Rhode Island Hospital, Providence, Rhode Island, United States
  • Zhuang, Shougang, Rhode Island Hospital, Providence, Rhode Island, United States
Background

The mixed-lineage leukemia 1 (MLL1)/WD-40 repeat protein 5 (WDR5) complex is a methyltransferase deemed a positive regulator of histone H3 lysine 4 trimethylation (H3K4me3) and functions as an oncogenic factor in many cancer types. The role of the MLL1/WDR5 complex in acute kidney injury (AKI) and renal epithelial cell death is still unclear. In this study, we investigated the role and mechanism of this complex in the apoptosis of renal epithelial cells following cisplatin exposure.

Methods

Cultured mouse kidney proximal tubular (TKPT) cells were exposed to cisplatin in the presence or absence of MM102, a MLL1/WDR5 protein–protein interaction inhibitor or small interfering RNAs (siRNA) specific targeting MLL1 or WDR5.

Results

Expression of MLL1, WDR5 and H3K4me3 as well as phospho-p53 and cleaved caspase 3 were increased whereas that of E-cadherin was decreased in cultured TKPT cells exposed to cisplatin in a time dependent manner. Inhibition of the MLL1/WDR5 complex with MM102 or siRNA-mediated silencing MLL1 or WDR5 attenuated cisplatin induced cleavage of caspase 3 and cell death, which was coincident with downregulation of p-p53 and preservation of E-cadherin expression. Inhibition of p53 by pifithrin-α also alleviated cisplatin-induced cell death and restored E-cadherin expression in TKPT cells with or without MM102 treatment. In contrast, activation of p53 by Nutlin potentiated TKPT cell death and E-cadherin repression. Moreover, siRNA mediated silencing of E-cadherin attenuated the protective effect of MM102 following cisplatin treatment while expression of p-p53 was not affected. Finally, we found that pharmacological inhibition of MLL1/WDR5 reduced cisplatin-induced phosphorylation of ataxia-telangiectasia mutated protein, ataxia telangiectasia and Rad3-related protein, checkpoint kinase 1 (Chk1), checkpoint kinase 2 (Chk2) and γ-H2AX, which are activated in response to DNA damage and associated with p53 transcriptional activation.

Conclusion

These data suggest that the MLL1/WDR5 complex may contribute to cisplatin-induced apoptosis of renal tubular epithelial cells by promoting p53-mediated E-cadherin repression following DNA damage. Targeting the MLL1/WDR5 complex may have a therapeutic potential for the treatment of cisplatin-induced AKI.

Funding

  • NIDDK Support