Abstract: SA-PO385

Phosphate Niclosamide Mitigates Renal Fibrosis through Inhibiting HIPK2 Expression

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 301 CKD: Risk Factors for Incidence and Progression

Authors

  • Zhen, Xin, Nanfang Hospital Southern Medical University, Guangzhou, China
  • Chang, Xiaoyan, Nanfang Hospital Southern Medical University, Guangzhou, China
Background

Renal fibrosis is the final common pathway of all kinds of progressive chronic kidney disease (CKD). However, there are no effective therapies to prevent or slow the progression of renal fibrosis. Recently, homeodomain interacting protein kinase 2 (HIPK2) has been identified as a key regulator in kidney fibrosis and idiopathic pulmonary fibrosis (IPF) that acts upstream of several major pro-fibrotic and pro-inflammatory pathways including TGF-β/Smad, Wnt/β-catenin, Notch pathway and NF-κB pathway, indicating that HIPK2 might be a potential target for anti-fibrosis therapy.Niclosamide is a Food and Drug Administration (FDA) approved oral antihelminthic drug used for treating most tapeworm infections .It has been shown that P-NICLO exerts antitumor function by targeting multiple signaling pathways including NF-κB, Wnt/β-catenin, and Notch pathway. Given the critical role of the above pathways in the pathogenesis of renal fibrosis, the aim of the present study is to explore the potential therapeutic effect of P-NICLO on renal fibrosis.

Methods

In vivo, male BALB/C mice were injected with ADR(12mg/kg).P-NICLO (30mg/kg/d) was injected 2 weeks after ADR for 3 weeks.UUO mice received intraperitoneal injection of P-NICLO (30mg/kg/d) from day 7 after operation for 7 days.
In vitro, NRK-52E or HK-2 cells reached approximately 60% confluence, pre-incubated with indicated amount of P-NICLO for 1 h followed by con-incubation with recombinant TGF-β1. WT-HIPK2 construct was transfected into HK-2 cells by using Lipofectamin 2000 Reagent 24 h after TGF-β1 (10ng/ml) and P-NICLO (0.4 µM) treatment.

Results

1.P-NICLO attenuates glomerular injury and interstitial fibrosis induced by ADR.
2.P-NICLO ameliorates established renal fibrosis and interstitial inflammation induced by UUO
3.P-NICLO inhibits multiple profibrotic signaling pathways include TGF-β/Smads,Wnt/β-catenin,NF-κB and Notch pathways in vitro and in vivo
4.P-NICLO inhibits HIPK2 transcription through interfering the binding of Smad3 to the promoter region of HIPK2 gene to inhibit the expression of pro-fibrosis markers

Conclusion

In summary, we have shown here that P-NICLO is effective in slowing the progression of renal fibrosis. Mechanistically, P-NICLO directly attenuated the activation of multiple pro-inflammatory and profibrotic signalings through suppressing TGF-β1-induced HIPK2 expression