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

Kapil Chaudhary, Rahul Shinde, Haiyun Liu, Jaya P. Gnana-Prakasam, Rajalakshmi Veeranan-Karmegam, Lei Huang, Buvana Ravishankar, Jillian Bradley, Nino Kvirkvelia, Malgorzata McMenamin, Wei Xiao, Daniel Kleven, Andrew L. Mellor, Michael P. Madaio, Tracy L. McGaha

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)5713-5724
Number of pages12
JournalJournal of Immunology
Volume194
Issue number12
DOIs
StatePublished - Jun 15 2015
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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