title: Amino acid metabolism inhibits antibody-driven kidney injury by inducing autophagy.
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.
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Augusta, GA 30912;
authors.forename: Kapil
authors.initials: K
authors.lastname: Chaudhary
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Augusta, GA 30912;
authors.forename: Rahul
authors.initials: R
authors.lastname: Shinde
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Augusta, GA 30912;
authors.forename: Haiyun
authors.initials: H
authors.lastname: Liu
authors.affiliation: Signaling and Angiogenesis Program, Georgia Regents University Cancer Center, Augusta, GA 30912;
authors.forename: Jaya P
authors.initials: JP
authors.lastname: Gnana-Prakasam
authors.affiliation: Signaling and Angiogenesis Program, Georgia Regents University Cancer Center, Augusta, GA 30912;
authors.forename: Rajalakshmi
authors.initials: R
authors.lastname: Veeranan-Karmegam
authors.affiliation: 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;
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Augusta, GA 30912;
authors.forename: Buvana
authors.initials: B
authors.lastname: Ravishankar
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Augusta, GA 30912;
authors.forename: Jillian
authors.initials: J
authors.lastname: Bradley
authors.affiliation: Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; and.
authors.forename: Nino
authors.initials: N
authors.lastname: Kvirkvelia
authors.affiliation: Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; and.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: McMenamin
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Augusta, GA 30912;
authors.forename: Wei
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Department of Pathology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kleven
authors.affiliation: 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.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Mellor
authors.affiliation: Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; and.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Madaio
authors.affiliation: 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.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: McGaha
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D001323:Autoantibodies / Q000276:immunology*; D001343:Autophagy / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D050199:Podocytes / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological
chemical_list: D000596:Amino Acids; D001323:Autoantibodies; D016207:Cytokines; C583637:IDO1 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases