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 journalArticle

15 Citations (Scopus)

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

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Autophagy
Kidney
Amino Acids
Antibodies
Wounds and Injuries
Indoleamine-Pyrrole 2,3,-Dioxygenase
Nephritis
Chronic Kidney Failure
Kidney Diseases
Stromal Cells
Phosphotransferases
Macrophages
Cytokines
Inflammation
Gene Expression
Enzymes
Serum

ASJC Scopus subject areas

  • Immunology

Cite this

Chaudhary, K., Shinde, R., Liu, H., Gnana-Prakasam, J. P., Veeranan-Karmegam, R., Huang, L., ... McGaha, T. L. (2015). Amino acid metabolism inhibits antibody-driven kidney injury by inducing autophagy. Journal of Immunology, 194(12), 5713-5724. https://doi.org/10.4049/jimmunol.1500277

Amino acid metabolism inhibits antibody-driven kidney injury by inducing autophagy. / Chaudhary, Kapil; Shinde, Rahul; Liu, Haiyun; Gnana-Prakasam, Jaya P.; Veeranan-Karmegam, Rajalakshmi; Huang, Lei; Ravishankar, Buvana; Bradley, Jillian; Kvirkvelia, Nino; McMenamin, Malgorzata; Xiao, Wei; Kleven, Daniel; Mellor, Andrew L.; Madaio, Michael P.; McGaha, Tracy L.

In: Journal of Immunology, Vol. 194, No. 12, 15.06.2015, p. 5713-5724.

Research output: Contribution to journalArticle

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 2015, 'Amino acid metabolism inhibits antibody-driven kidney injury by inducing autophagy', Journal of Immunology, vol. 194, no. 12, pp. 5713-5724. https://doi.org/10.4049/jimmunol.1500277
Chaudhary K, Shinde R, Liu H, Gnana-Prakasam JP, Veeranan-Karmegam R, Huang L et al. Amino acid metabolism inhibits antibody-driven kidney injury by inducing autophagy. Journal of Immunology. 2015 Jun 15;194(12):5713-5724. https://doi.org/10.4049/jimmunol.1500277
Chaudhary, Kapil ; Shinde, Rahul ; Liu, Haiyun ; Gnana-Prakasam, Jaya P. ; Veeranan-Karmegam, Rajalakshmi ; Huang, Lei ; Ravishankar, Buvana ; Bradley, Jillian ; Kvirkvelia, Nino ; McMenamin, Malgorzata ; Xiao, Wei ; Kleven, Daniel ; Mellor, Andrew L. ; Madaio, Michael P. ; McGaha, Tracy L. / Amino acid metabolism inhibits antibody-driven kidney injury by inducing autophagy. In: Journal of Immunology. 2015 ; Vol. 194, No. 12. pp. 5713-5724.
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