Amino acid metabolism inhibits antibody-driven kidney injury by inducing autophagy.
Amino acid metabolism inhibits antibody-driven kidney injury by inducing autophagy.
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DOI：
10.4049/jimmunol.1500277
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发表时间：
2015-06-15
期刊：
影响因子：
--
通讯作者：
McGaha TL
中科院分区：
文献类型：
--
作者：
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
炎症性肾病是导致终末期肾功能衰竭的主要临床问题。在这里，我们展示了抗体介导的炎症性肾损伤和肾脏疾病在小鼠肾毒性血清肾炎(NTN)模型中被氨基酸代谢和保护性自噬反应所抑制。代谢信号是由干扰素-γ介导的诱导吲哚胺2，3双加氧酶1(IDO 1)酶活性驱动的，随后激活依赖于eIF2α激酶总控制不可降压2(GCN2)的应激反应。在抗体诱导的肾小球炎症的早期阶段，GCN2的激活抑制了肾小球促炎细胞因子的产生，并减少了巨噬细胞对肾脏的募集。此外，抑制Ido1或GCN2的自噬或基因消融将抗体诱导的自限性肾炎转化为致命的终末期肾脏疾病。相反，增加肾脏IDO1活性或用GCN2激动剂治疗小鼠可诱导自噬并保护小鼠免受肾炎性肾损害。最后，抗体驱动的肾病患者的肾组织显示IDO1丰度增加，GCN2激活和自噬诱导。因此，这些发现支持这样的假设，即肾小球基质细胞中的IDO-GCN2通路是一种关键的负反馈机制，通过诱导自噬来限制炎症肾脏病理。
Inflammatory kidney disease is a major clinical problem that can result in end-stage renal failure. Here we show that antibody mediated inflammatory kidney injury and renal disease in a mouse nephrotoxic serum nephritis (NTN) 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 antibody induced glomerular inflammation. Further, inhibition of autophagy or genetic ablation of Ido1 or Gcn2 converted antibody-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 antibody-driven nephropathy showed increased IDO1 abundance, GCN2 activation and autophagy induction. 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 pathology by inducing autophagy.
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影响因子：
3.7
作者：
Fang L;Zhou Y;Cao H;Wen P;Jiang L;He W;Dai C;Yang J
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DOI：
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发表时间：
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期刊：
B LYMPHOCYTES AND AUTOIMMUNITY
影响因子：
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16
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影响因子：
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