The tryptophan-metabolizing enzyme indoleamine 2,3-dioxygenase 1 regulates polycystic kidney disease progression.
The tryptophan-metabolizing enzyme indoleamine 2,3-dioxygenase 1 regulates polycystic kidney disease progression.
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DOI：
10.1172/jci.insight.154773
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发表时间：
2023-01-10
期刊：
影响因子：
8
通讯作者：
Hopp, Katharina
中科院分区：
文献类型：
--
作者：
Nguyen, Dustin T.;Kleczko, Emily K.;Dwivedi, Nidhi;Monaghan, Marie-Louise T.;Gitomer, Berenice Y.;Chonchol, Michel B.;Clambey, Eric T.;Nemenoff, Raphael A.;Klawitter, Jelena;Hopp, Katharina
常染色体显性遗传性多囊肾病（ADPKD）是最常见的单基因肾病，其特征是表型变异超过基因效应。代谢和免疫细胞功能失调是关键的疾病调节因素。色氨酸代谢物犬尿氨酸通过吲哚胺2，3-双加氧酶1（IDO 1）产生，是已知的免疫调节剂。在这里，我们研究色氨酸代谢的作用，PKD使用orthopathy疾病模型（C57 BL/6 J Pkd 1 RC/RC）。我们发现与野生型相比，Pkd 1 RC/RC肾脏中犬尿氨酸和IDO 1水平升高。此外，IDO 1水平在ADPKD细胞系中增加。Pkd 1 RC/RC动物的遗传Ido 1缺失导致PKD严重程度降低，通过囊性指数和相对于体重标准化的肾脏重量百分比进行测量。与犬尿氨酸的免疫调节作用一致，与对照组相比，Pkd 1 RC/RC; Ido 1-/-小鼠的囊性免疫微环境（CME）出现显著变化。肾脏巨噬细胞数量减少，CD 8 + T细胞数量增加，均为已知的PKD调节剂。此外，在Pkd 1 RC/RC小鼠和肾特异性Pkd 2基因敲除小鼠中，与对照组相比，IDO 1药理学抑制导致PKD严重程度较低，CME的变化与遗传模型中的变化相似。我们的数据表明，色氨酸代谢在ADPKD中失调，其抑制导致CME的变化并减缓疾病进展，使IDO 1成为ADPKD的治疗靶点。
Autosomal dominant polycystic kidney disease (ADPKD), the most common monogenic nephropathy, is characterized by phenotypic variability that exceeds genic effects. Dysregulated metabolism and immune cell function are key disease modifiers. The tryptophan metabolites, kynurenines, produced through indoleamine 2,3-dioxygenase 1 (IDO1), are known immunomodulators. Here, we study the role of tryptophan metabolism in PKD using an orthologous disease model (C57BL/6J Pkd1RC/RC). We found elevated kynurenine and IDO1 levels in Pkd1RC/RC kidneys versus wild type. Further, IDO1 levels were increased in ADPKD cell lines. Genetic Ido1 loss in Pkd1RC/RC animals resulted in reduced PKD severity, as measured by cystic index and percentage kidney weight normalized to body weight. Consistent with an immunomodulatory role of kynurenines, Pkd1RC/RC;Ido1–/– mice presented with significant changes in the cystic immune microenvironment (CME) versus controls. Kidney macrophage numbers decreased and CD8+ T cell numbers increased, both known PKD modulators. Also, pharmacological IDO1 inhibition in Pkd1RC/RC mice and kidney-specific Pkd2-knockout mice with rapidly progressive PKD resulted in less severe PKD versus controls, with changes in the CME similar to those in the genetic model. Our data suggest that tryptophan metabolism is dysregulated in ADPKD and that its inhibition results in changes to the CME and slows disease progression, making IDO1 a therapeutic target for ADPKD.
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DOI：
10.1177/1178646917694600
发表时间：
2017
期刊：
International journal of tryptophan research : IJTR
影响因子：
--
作者：
Debnath S;Velagapudi C;Redus L;Thameem F;Kasinath B;Hura CE;Lorenzo C;Abboud HE;O'Connor JC
通讯作者：
O'Connor JC
影响因子：
16.6
作者：
Flowers EM;Sudderth J;Zacharias L;Mernaugh G;Zent R;DeBerardinis RJ;Carroll TJ
通讯作者：
Carroll TJ
影响因子：
6.9
作者：
Favennec, Marie;Hennart, Benjamin;Poulain-Godefroy, Odile
通讯作者：
Poulain-Godefroy, Odile
影响因子：
15.9
作者：
Hopp, Katharina;Ward, Christopher J.;Harris, Peter C.
通讯作者：
Harris, Peter C.
影响因子：
3.7
作者：
Garcia-Gonzalez, Miguel A.;Outeda, Patricia;Watnick, Terry
通讯作者：
Watnick, Terry