Background/Purpose:

The receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor that interacts with multiple ligands such as high mobility group box 1 (HMGB1) and is involved in various innate immune responses. The soluble form of RAGE (sRAGE) can bind to RAGE-ligands in the extracellular space, and thus competitively inhibit the binding of ligands to the membrane-bound form of RAGE (mRAGE), resulting in a reduction of the inflammation induced by NF-κB activation. We investigated the efficacy of different doses of the Fc-portion-conjugated sRAGE on nephritis in lupus-prone mice in comparison with the efficacy of combination therapy of mycophenolate mofetil plus prednisolone.

Methods:

Twenty-eight female NZB/WF1 mice were divided into five groups (untreated; 0.5, 1, 2 μg of sRAGE; mycophenolate mofetil plus prednisolone). Proteinuria and histological damage were evaluated. Immune-complex deposition and the nuclear translocation of NF-κB in kidney tissues were assessed by immunofluorescence staining. Serum concentrations of anti-dsDNA and IgG subclasses were also measured. The population of T cells was evaluated using a fluorescence-activated cell sorter and ICAM-1 and VCAM-1 expression in kidney tissues was assessed by immunohistochemical staining.

Results:

In comparison with untreated mice, mice treated with 1 or 2 μg of sRAGE showed significantly reduced proteinuria and improved histological renal damage, with efficacy comparable to that of combination therapy. Treatment with 1 or 2 μg of sRAGE significantly reduced immune-complex accumulation; decreased the serum concentrations of anti-dsDNA, IgG2a, IgG2b and IgG3; and interrupted the nuclear translocation of NF-κB in kidney tissues, leading to reduced ICAM-1 and VAM-1 expression. Furthermore, sRAGE effectively modified T cell populations.

Conclusion:

sRAGE significantly improved nephritis in lupus-prone mice, with efficacy comparable to that of standard induction treatment for lupus nephritis. These data suggest that sRAGE have anti-inflammatory effects in lupus nephritis pathophysiology and could serve as a potent additional therapy for lupus nephritis.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/soluble-receptor-for-advanced-glycation-end-products-alleviates-nephritis-in-nzbwf1-mice/