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Abstract: FR-PO698

Involvement of Kynurenine Metabolizing Enzymes and Its Metabolites in Antibody-Mediated Glomerulonephritis

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • Umeda, Ryosuke, Fujita Ika Daigaku, Toyoake, Aichi, Japan
  • Hasegawa, Midori, Fujita Ika Daigaku, Toyoake, Aichi, Japan
  • Tsuboi, Naotake, Fujita Ika Daigaku, Toyoake, Aichi, Japan
Background

Tryptophan (TRP) is eventually metabolized to NAD in kynurenine pathway (KP), and its metabolites (Figure) potentially exert many biological activities in immune system. The objective of the current study is to elucidate the role of TRP metabolism in the progression of glomerulonephritis.

Methods

We introduced antibody mediated glomerulonephritis by administration of rabbit anti-mouse nephrotoxic serum (NTS-GN) in mouse strains deficient in KP-related enzymes including indoleamine 2,3-dioxygenase 1, 2 (IDO1-/-, IDO2-/-), and kynurenine 3-monooxygenase (KMO-/-) and performed functional and histological analyses in diseased kidneys. For the therapeutic intervention, we administrated kynurenic acid (KYNA) into IDO1-/- with NTS-GN. In vitro, we analyzed morphology of bone marrow derived neutrophils on immune complexes (ICs).

Results

IDO1-/- demonstrated severe renal dysfunction and histological glomerular damage than WT, while those in IDO2-/- were comparable with WT. Conversely, crescent formation was significantly less in KMO-/- mice. Glomerular accumulation of neutrophils was significantly more in IDO1-/- mice, but less in KMO-/- mice. Neutrophils presenting “spread” morphology among attaching cells on ICs was significantly increased in IDO1-/-, whereas it was reduced in KMO-/-. Administration of KYNA into the diseased IDO1-/- significantly diminished glomerular crescent formation, which associated with the amelioration of renal dysfunction. Moreover, KYNA treated IDO1-/- neutrophils demonstrated less percentage of “spread” cells on IC-coated dishes than non-treated cells.

Conclusion

IDO1/KMO-mediated alterations of TRP metabolism involve in the disease activity of NTS-GN. Of note, KYNA negatively regulates to the disease pathogenesis by the alteration of IC-mediated neutrophil activity.