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Abstract: SA-PO843

Therapeutic Effect of Nanoparticle-Mediated shRNA Delivery in Lupus Nephritis Mice

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • Shao, Wenhai, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
  • Zhen, Yuxuan, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
  • Adams, David Erwin, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
Background

Lupus nephritis (LN) is the most common and severe manifestation of systemic lupus erythematosus (SLE). LN pathogenesis is complex and incomplete understood. Therapy approach are predominantly nonspecific immunosuppressive medications. More effective drugs with favorable safety profiles are urgently needed. MRL/lpr mice develop lupus nephritis that mostly assemble disease manifestation in lupus patients. WD repeats and FYVEdomain-containing protein 1 (WDFY1) is an adaptor protein involving in inflammatory pathways in LN.

Methods

Protein levels of WDFY1 were analyzed by Western blot and immunofluorescent staining in the kidney of nephritic MRL/lpr mice and lupus nephritis patients. Lupus-like disease was first induced in C57BL/6 mice by ip administration with 1 X 108 splenocytes from bm12 mice. Serum autoantibody levels were measured by ELISA. Germinal center reaction and cell subtypes were analyzed. Twelve-week old MRL/lpr mice were treated with nanoparticle encapsuled WDFY1-shRNA for 5 weeks. Renal pathology, immune complex deposition, and complement activation were examined.

Results

Significantly enhanced WDFY1 expression was detected in the kidney of MRL/lpr mice compared to the age/sex-matched MRL/MpJ mice. The expression levels also correlated with the nephritis disease activity. Kidney sections from LN patients also showed increased WDFY1 expression compared to kidney samples from healthy controls. B6.WT mice developed increased levels of anti-dsDNA and anti-chromatin autoAbs after receiving bm12 splenocytes. AutoAb production was significantly diminished in B6.WDFY1-KO mice receiving the same dose of bm12 splenocytes. Most importantly, MRL/lpr mice treated with nanoparticle encapsuled WDFY1-shRNA showed improved kidney function with significantly decreased BUN and proteinuria.

Conclusion

Observations made here support the usefulness of WDFY1 for the treatment of lupus and lupus nephritis. Results may lead to more effective and safer molecule-specific approaches.

Funding

  • NIDDK Support