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J Immunol. 2015 Jun 15;194(12):5713-24. doi: 10.4049/jimmunol.1500277. Epub 2015 May 15.

Amino acid metabolism inhibits antibody-driven kidney injury by inducing autophagy.

Author information

1
Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Augusta, GA 30912;
2
Signaling and Angiogenesis Program, Georgia Regents University Cancer Center, Augusta, GA 30912;
3
Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Augusta, GA 30912; Department of Radiology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912;
4
Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; and.
5
Department of Pathology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912.
6
Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Augusta, GA 30912; Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; and.
7
Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Augusta, GA 30912; Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; and tmcgaha@gru.edu.

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.

Comment in

PMID:
25980011
PMCID:
PMC4458436
DOI:
10.4049/jimmunol.1500277
[Indexed for MEDLINE]
Free PMC Article

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