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Kidney Week

Abstract: PO2475

Inhibition of RNA-Binding Protein HuR Protects Kidney from Ischemia-Reperfusion-Induced Injury and Fibrosis

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Huang, Zhimin, University of Utah Health, Salt Lake City, Utah, United States
  • Liu, Simeng, University of Utah Health, Salt Lake City, Utah, United States
  • Huang, Yufeng, University of Utah Health, Salt Lake City, Utah, United States
Background

Upregulation of an RNA-binding protein HuR has been implicated in glomerular diseases both in patients and in animal models. Herein, we further evaluated whether upregulation of HuR occurs in and promotes renal tubular injury and subsequent fibrosis by using a renal ischemia/reperfusion (IR) mouse model and a selective HuR inhibitor, KH3.

Methods

All mice were received unilateral renal IR surgery for 35 min. The contralateral kidneys without surgery served as controls. Mice were then randomly assigned into either vehicle or KH3-treated groups (n=5/group). KH3 was given via daily intraperitoneal injection from day 3 after IR at the dose of 50 mg/kgWB/day to day 14. In additon the effect of HuR inhibition on TGFß-induced tubular cell injury was further investigated in vitro.

Results

IR-injured kidneys showed a significant upregulation of HuR in tubular and tubulointerstitial cells determined by postive cytoplasmic staining of HuR and western blot assay, which was accompanied by extensive tubular damage and fibrosis. However, KH3-treated and IR-injured kidneys exhibited greatly reduced damage and fibrosis, and this correlated with a reduction in renal expression of profibrotic molecules, inflammatory cytokines, NADPH oxidases, and markers for cell proliferation, tubular epithelial-to-mesenchymal transition (EMT), and apoptosis. A panel of 760 fibrosis-associated genes were further assessed, revealing that 519 genes in mouse kidney following IR injury changed their expression and 71.3% of those genes that are involved in 50 annotated pathways were ameliorated when treated with KH3. Among those, TGFß1 as a HuR target was elevated in the IR-injured kidney. KH3 abrogated TGFβ1-induced tubular HuR cytoplasmic translocation and subsequent tubular EMT in cultured HK-2 cells.

Conclusion

These results suggest that upregulation of HuR contributes to renal tubular injury and fibrosis by dysregulating multiple pro-fibrotic pathways. HuR-targeted inhibitory therapeutics offer a promising novel treatment in the future for preventing or reversing the progression of CKD.

Funding

  • NIDDK Support