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Abstract: FR-PO593

Inhibition of VEGFR3 by SAR131672 Decreases Renal Inflammation and Lymphangiogenesis in the Murine Lupus Nephritis Model

Session Information

Category: Glomerular Diseases

  • 1302 Glomerular Diseases: Immunology and Inflammation

Authors

  • Li, Wenjia, Jeonbuk National University Medical School, Jeonju, Jeollabuk-do , Korea (the Republic of)
  • Wang, Tian, Jeonbuk National University Medical School, Jeonju, Jeollabuk-do , Korea (the Republic of)
  • Yeom, Jihyun, Jeonbuk National University Medical School, Jeonju, Jeollabuk-do , Korea (the Republic of)
  • Kang, Kyung Pyo, Jeonbuk National University Medical School, Jeonju, Jeollabuk-do , Korea (the Republic of)
Background

Lupus nephritis (LN) is an immune complex glomerulonephritis that develops as a frequent and potentially dismal manifestation of SLE. Lymphangiogenesis is the proliferation of pre-existing lymphatic vessels (LVs), which regulate tissue fluid homeostasis and immune cell trafficking, responding to the tissue environment. In this study, we have evaluated the therapeutic effect of the VEGFR3 inhibitor, SAR 131672, on the murine lupus nephritis model by regulation of inflammation and lymphangiogenesis.

Methods

Seven to eight-week-old male BALB/c mice were used in this experiment. The back area's skin was shaved and treated topically three times per week, with 100 μg of resiquimod in 100 μl of acetone for eight weeks and concomitantly treatment of VEGFR3 inhibitor, SAR 131672 by oral gavage. We evaluated renal histology and immunofluorescent staining for inflammatory cells and lymphatic vessels. We also assessed inflammatory cytokines and, chemokines, lymphangiogenic factors by qRT-PCR.

Results

Eight weeks of topical treatment of resiquimod to Balb/c mice induces lupus-like symptoms such as weight loss, splenomegaly, and glomerular immune complexes deposit such as IgG, IgM, and C3 in immunofluorescent staining. Histologically, glomerular mesangial cell proliferation and increased inflammatory cells in tubulointerstitial areas were noted in the H&E stain. Inhibiting VEGFR3 by oral SAR131672 treatment decreases glomerular and tubulointerstitial inflammation and LYVE-1 positive lymphatic vessels. The proinflammatory cytokines and chemokines such as ICAM-1, VCAM-1, MCP-1, CCL19, CCL21, CCR7, CXCL13, and BAFF mRNA levels were increased compared with the vehicle-treated group. Treatment SAR131672 decreases proinflammatory cytokines and chemokine.

Conclusion

VEGFR3 inhibition by SAR131672 decreases the resiquimod-induced lupus nephritis model by regulating inflammation and lymphangiogenesis.

Funding

  • Government Support – Non-U.S.