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Abstract: FR-PO235

GSK343 Inhibits EZH2 to Promote MST1 Expression and Confers Neuroprotection in Kidney Failure-Induced Hypercalcemia

Session Information

  • Pharmacology
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Pharmacology (PharmacoKinetics‚ -Dynamics‚ -Genomics)

  • 1900 Pharmacology (PharmacoKinetics‚ -Dynamics‚ -Genomics)

Authors

  • Cao, Yaochen, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Li, Xitong, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
Background

GSK343 is a specific inhibitor of EZH2 which has been highlighted to serve as a potential therapeutic target for kidney diseases. We sought to examine the underlying mechanism of GSK343 in the nerve damage induced by kidney failure-associated hypercalcemia.

Methods

We first established an in vivo adenine diet-induced CKD model in C57BL/6N mice. After administration of GSK343, oe-EZH2, oe-MST1 and oe-YAP1, disease activity index, serum biochemical indexes, blood calcium and nerve function of mice were evaluated, as well as the expression of M1 marker (iNOS) and M2 marker gene (Arg1). Gain function studies were all employed in renal tubular epithelial cells TCMK-1 to elucidate the mechanism of GSK343/EZH2/MST1/YAP1 in the processes of nerve damage induced by kidney failure-associated hypercalcemia.

Results

GSK343 polarized macrophages toward M2 phenotype and thus arrested the resultant nerve damage from kidney failure-induced hypercalcemia. GSK343 reduced the expression of EZH2 and triggered an increase in the expression of MST1. In addition, MST1 overexpression reduced the expression of YAP1, thereby promoting M2 polarization of macrophages and attenuating the nerve damage induced by hypercalcemia. Furthermore, GSK343 promoted macrophages polarized to M2 phenotype and attenuated nerve damage by regulating the EZH2/MST1/YAP1 axis.

Conclusion

Overall, our findings suggest that GSK343 may be a novel mechanism underlying the M2 polarization of macrophages and the resultant nerve damage from kidney failure-induced hypercalcemia.

Funding

  • Government Support – Non-U.S.