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Amino Acid Metabolism Inhibits Antibody-Driven Kidney Injury by Inducing Autophagy

Lookup NU author(s): Dr Lei HuangORCiD

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Abstract

Inflammatory kidney disease is a major clinical problem that can result in end-stage renal failure. In this article, we show that Ab-mediated inflammatory kidney injury and renal disease in a mouse nephrotoxic serum nephritis model was inhibited by amino acid metabolism and a protective autophagic response. The metabolic signal was driven by IFN-γ–mediated induction of indoleamine 2,3-dioxygenase 1 (IDO1) enzyme activity with subsequent activation of a stress response dependent on the eIF2α kinase general control nonderepressible 2 (GCN2). Activation of GCN2 suppressed proinflammatory cytokine production in glomeruli and reduced macrophage recruitment to the kidney during the incipient stage of Ab-induced glomerular inflammation. Further, inhibition of autophagy or genetic ablation of Ido1 or Gcn2 converted Ab-induced, self-limiting nephritis to fatal end-stage renal disease. Conversely, increasing kidney IDO1 activity or treating mice with a GCN2 agonist induced autophagy and protected mice from nephritic kidney damage. Finally, kidney tissue from patients with Ab-driven nephropathy showed increased IDO1 abundance and stress gene expression. Thus, these findings support the hypothesis that the IDO–GCN2 pathway in glomerular stromal cells is a critical negative feedback mechanism that limits inflammatory renal pathologic changes by inducing autophagy.


Publication metadata

Author(s): Chaudhary K, Shinde R, Liu H, Gnana-Prakasam JP, Veeranan-Karmegam R, Huang L, Ravishankar B, Bradley J, Kvirkvelia N, McMenamin M, Xiao W, Kleven D, Mellor AL, Madaio MP, McGaha TL

Publication type: Article

Publication status: Published

Journal: Journal of Immunology

Year: 2015

Volume: 194

Issue: 12

Pages: 5713-5724

Print publication date: 15/06/2015

Online publication date: 15/05/2015

Acceptance date: 01/05/2015

ISSN (print): 0022-1767

ISSN (electronic): 1550-6606

Publisher: American Association of Immunologists

URL: https://doi.org/10.4049/jimmunol.1500277

DOI: 10.4049/jimmunol.1500277

PubMed id: 25980011


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