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Abstract: FR-PO1042

TP53RK in Fibroblasts Drives the Progression of CKD by Phosphorylating Birc5

Session Information

Category: CKD (Non-Dialysis)

  • 2303 CKD (Non-Dialysis): Mechanisms


  • Wu, Mengqiu, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
  • Jia, Zhanjun, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
  • Zhang, Aihua, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, China

Renal fibrosis is a common characteristic of various chronic kidney diseases (CKDs) driving the loss of renal function. During this pathological process, proliferation and activation of interstitial fibroblasts chiefly determine the extent of renal fibrosis. TP53RK is an atypical protein kinase and an important component of the EKC/KEOPS complex. Recently, TP53RK was identified as novel monogenetic cause of Galloway–Mowat syndrome. However, no experimental evidence confirmed the role of TP53RK in CKDs.


Expression and localization of TP53RK was evaluated in kidneys of CKD patients and mice with unilateral ureteral obstruction (UUO) and unilateral ischemia reperfusion (UIR). Then, the specific function of fibroblast TP53RK in CKD was determined with fibroblast specific TP53RK knockout mice with UUO or UIR and TGF-β1-treated renal interstitial fibroblasts (NRK-49F). Furthermore, co-immunoprecipitation and immunofluorescent staining were applied to determine the co-localization and interaction between TP53RK and Birc5. UUO mice with global Birc5 knockdown were employed to specify the role and downstream mechanism of Birc5 in renal fibrosis. Finally, TP53RK inhibitor fusidic acid and Birc5 specific inhibitor YM-155 were tested in UUO mice to evaluate the translational potential of pharmacological blockade in treating CKD.


P53RK was upregulated in fibrotic human and animal kidneys with a positive correlation to kidney dysfunction and fibrotic markers. Specifically, TP53RK was up-regulated in interstitial fibroblasts of fibrotic kidneys. Fibroblasts specific deletion of TP53RK could mitigate renal fibrosis in UUO and UIR mice models. In vitro, knocking down of TP53RK attenuated activation and proliferation of NRK-49F. Mechanistic investigations revealed that TP53RK phosphorylated Birc5 and facilitated its nuclear translocation, which displayed a pro-fibrotic effect possibly via activating PI3K/Akt and MAPK pathways. Moreover, pharmacologically inhibiting TP53RK and Birc5 using fusidic acid and YM-155 respectively both ameliorated kidney fibrosis in UUO mice.


These findings demonstrate that activated TP53RK/Birc5 signaling promotes the proliferation and activation of renal interstitial fibroblasts, thus driving CKD progression. A genetic or pharmacological blockade of this axis serves as a potential strategy for retarding fibrosis in CKD.


  • Government Support – Non-U.S.