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Abstract: FR-PO1060

Therapeutic Strategies Targeting RAGE Prevent Kidney Injury and Renal Fibrosis in Systemic Lupus Erythematosus

Session Information

Category: CKD (Non-Dialysis)

  • 2303 CKD (Non-Dialysis): Mechanisms


  • Taguchi, Kensei, Division of Nephrology, Kurume University School of Medicine, Kurume, Japan
  • Moriyama, Tomofumi, Division of Nephrology, Kurume University School of Medicine, Kurume, Japan
  • Kodama, Goh, Division of Nephrology, Kurume University School of Medicine, Kurume, Japan
  • Fukami, Kei, Division of Nephrology, Kurume University School of Medicine, Kurume, Japan

Lupus nephritis (LN) occurs in up to 60% of patients with systemic lupus erythematosus (SLE). Despite of current development of immunosuppressant agents, LN still impairs the survival and quality of life in SLE patients. Receptor for advanced glycation endproducts (RAGE) is a multi-ligand receptor is associated with innate immune system. In the present study, we examined whether RAGE is involved in the development of LN. Further, we explored the therapeutic impact of DNA-aptamer directed against RAGE (RAGE-apt) on lupus-related kidney injury.


[Protocol 1] RAGE expression in kidneys and urinary RAGE excretion (uRAGE) were determined at several time points by real-time PCR and ELISA, respectively in MRL/lpr, SLE-prone mice. [Protocol 2] LN was induced by peritoneally injecting pristane in wild type and RAGE globally knockout mice. [Protocol 3] MRL/lpr mice were subcutaneously administrated with RAGE-apt or Control-aptamer (Ctrl-apt) for 10weeks. [Protocol 4] Isolated proximal tubules from wild type and RAGE knockouts were treated with CpG-ODN for 7 days in the presence or absence of chroloquine.


[Protocol 1] uRAGE was increased since 8-week-old MRL/lpr mice, and was positively correlated with urinary NAG, a tubular injury marker. RAGE was upregulated in distal tubules in early stage, meanwhile RAGE started to be extensively expressed in nephron at later time point. In proximal tubules (PTC), RAGE was co-localized with cathepsine D, a lysosomal aspartyl protease, and Rab7, a marker of late endocytosis, suggesting that PTC RAGE is involved in endosome pathway. [Protocol 2] Pristane-induced kidney injury and renal fibrosis were attenuated in RAGE knockouts with reduction in systolic blood pressure. [Protocol 3] Administration of RAGE-apt reduced systolic blood pressure and attenuated renal dysfunction. Expression levels of IL-6, TNF-a, and MCP-1 were inhibited by RAGE-apt, but not Ctrl-apt, in MRL/lpr mice. [Protocol 4] α-SMA was upregulated in wild type primary PTC, but not RAGE KO primary PTC, which was prevented by chroloquine, suggesting that the protective effect of RAGE inhibition is possibly through endosome-lysosome pathway.


RAGE could be involved in the pathogenesis of LN, and RAGE-apt can be potential to become a promising therapeutic option for preventing the development of LN.