133. Role of kynurenine metabolizing enzymes and tryptophan metabolites in antibody mediated glomerulonephritis.
Creators: name: Umeda1, Ryosuke
name: Naotake Tsuboi1
Publisher: name: Zenodo
Year: 2022
Subjects: Vasculitis
ANCA
Abstracts
Giant Cell Arthritis
MPA
GPA
EGPA
Takayasu
IgA vasculitis

description: <strong>Background:</strong> Tryptophan (TRP), which is one of the essential amino acids, is eventually metabolized to to nicotinamide adenine dinucleotide in kynurenine pathway, and its intermediate metabolites (Figure) potentially exert many biological activities. Although there are several studies indicating the involvement of indoleamine 2.3 dioxygenase (IDO), a rate limiting enzyme of kynurenine pathway, in onco-immunology, precise roles of TRP metabolism in autoimmune disorder is still controversial. For example, pharmaceutical inhibition of IDO for rheumatoid arthritis resulted in contradiction depending on the context of exploited animal models. The objective of the current study is to elucidate the role of TRP metabolism in the progression of antibody mediated glomerulonephritis by using mice deficient in TRP-metabolizing enzymes involved in kynurenine pathway (KP). <strong>Methods:</strong> We introduced antibody mediated crescentic glomerulonephritis by intravenous administration of rabbit anti-mouse nephrotoxic serum (NTS-GN) in several mouse strains deficient in KP-related enzymes (C57BL/6 mice background IDO1<sup>-/-</sup>, IDO2<sup>-/-</sup>, and kynurenine 3-monooxygenase; KMO<sup>-/-</sup>) and in those wild-type mice (WT), and assessed kidney function (urinary protein, serum Cr and BUN) and kidney histology at day7 and 14. We intraperitoneally administrated clodronate-liposome for macrophage depletion and exogenous kynurenic acid (KYNA) for therapeutic intervention into IDO1<sup>-/-</sup> with NTS-GN every other day until day10. In vitro, we analysed morphology of bone marrow derived neutrophils from IDO1<sup>-/-</sup>, IDO2<sup>-/-</sup>, KMO<sup>-/-</sup> or of KYNA-treated cells on immune-complex (IC) formed by BSA-anti-BSA antibody. <strong>Results:</strong> IDO1<sup>-/-</sup> demonstrated severe renal dysfunction and histological glomerular damage (increased crescent formation rate and PAS-positive area) starting on day7 compared to WT. On the other hands, the functional and histological kidney damages in IDO2<sup>-/-</sup> was comparable to those in WT, and conversely, crescent formation at week 2 was significantly less in KMO<sup>-/-</sup> mice than in WT. Moreover, glomerular accumulation of esterase+ neutrophils was significantly more in IDO1<sup>-/-</sup> mice, but less in KMO<sup>-/-</sup> mice than in WT. Depletion of macrophages significantly ameliorated glomerular crescent formation in IDO1<sup>-/-</sup> mice. The percentage of neutrophils presenting “spread” morphology among attaching cells on IC in IDO1<sup>-/-</sup> was significantly increased, whereas it in KMO<sup>-/-</sup> was reduced compared to WT. Treatment of KYNA in IDO1<sup>-/-</sup> with NTS-GN significantly diminished glomerular crescent formation, which associated with the amelioration of renal dysfunction, at day10. KYNA-treated IDO1<sup>-/-</sup> neutrophils demonstrated less percentage of “spread” cells on IC-coated dishes than non-treated cells. <strong>Conclusions</strong>: Our data suggests that IDO1 or KMO-mediated alterations of TRP metabolism particularly in macrophages and neutrophils involve in the disease activity of NTS-GN. In addition, KYNA may contribute to the improvement of antibody-mediated glomerular damage by altering neutrophil activity in response to ICs.<br> <strong>Disclosures:</strong> None.