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Abstract: FR-PO377

Novel Molecular Therapy of Diabetic Nephropathy by Repurposing Niclosamide to Modulate Renal RNA-Binding Protein HuR

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Zhuang, Lili, University of Utah Health, Salt Lake City, Utah, United States
  • Tsai, Xiao-Qing Erica, University of Utah Health, Salt Lake City, Utah, United States
  • Wang, Zhou, University of Utah Health, Salt Lake City, Utah, United States
  • Huang, Yufeng, University of Utah Health, Salt Lake City, Utah, United States
Background

Hu antigen R (HuR) influences the expression of genes involved in pathways critical to the pathogenesis of diabetic nephropathy (DN). We identified a FAD-approved anthelmintic drug, niclosamide (NCS), as a novel inhibitor of HuR. This study sought to determine whether HuR- targeted therapeutics with NCS are therapeutic for DN.

Methods

Four groups of uninephrectomized mice with normal control and diabetic db/db mice without treatment but being terminated at 14 and 22 wks respectively, or treated with NCS (20mg/kg daily via i.p.) from wks 18 to 22 were included.

Results

A significantly increased HuR expression was observed in diabetic kidneys from both patients and db/db mice, while the latter was inhibited by NCS treatment. Immunofluorescent staining for HuR confirmed the Western blot measurement. Untreated db/db mice developed progressive albuminuria and glomerular mesangial matrix expansion between age of weeks 14 and 22, associated with increased renal production of fibronectin and a-smooth muscle actin but decreased glomerular WT-1+-podocytes and nephrin expression. NCS treatment did not affect mouse body weight but reduced blood HbA1c levels (10.8±1.0 in treated db/db vs. 13.4±0.93% in db/db, P<0.05), arrested the increases in albuminuria, markers of glomerulosclerosis and podocyte injury seen in db/db mice. Renal expressions of NF-κBp65, TNF-a, MCP-1, Nox2, and urine TBARS levels, the markers of inflammation and oxidative stress, were increased during disease progression in db/db mice, which were halted by NCS treatment (P<0.05). In addition, a downstream factor of the Wnt signaling pathway, known as WNT1-inducible signaling pathway protein 1 (WISP1), has been identified as one of key downstream mediators of HuR-dependent action and found to be markedly increased by 3.2 fold in db/db mouse kidneys at 22 wks, compared with non-diabetic controls, which was abrogated by NCS treatment, approaching to normal levels.

Conclusion

These results indicate that inhibition of HuR with NCS is therapeutic for DN through improving hyperglycemia and renal inflammation and oxidative stress. The efficacy of NCS in reducing renal WISP1 expression and action may also contribute to its reno-protective effect. Our study provides a proof-of-concept for re-purposing HuR inhibitor as a novel intervention therapy for progressive DN.

Funding

  • NIDDK Support