Hypoxic preconditioning protects against ischemic kidney injury through the IDO1/kynurenine pathway.
Hypoxic preconditioning protects against ischemic kidney injury through the IDO1/kynurenine pathway.
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DOI：
10.1016/j.celrep.2021.109547
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发表时间：
2021-08-17
期刊：
影响因子：
8.8
通讯作者：
Kapitsinou PP
中科院分区：
文献类型：
--
作者：
Torosyan R;Huang S;Bommi PV;Tiwari R;An SY;Schonfeld M;Rajendran G;Kavanaugh MA;Gibbs B;Truax AD;Bohney S;Calcutt MW;Kerr EW;Leonardi R;Gao P;Chandel NS;Kapitsinou PP
长时间的细胞缺氧导致能量衰竭和死亡。然而，亚致死性缺氧可触发称为缺氧预适应的适应性反应。虽然脯氨酰羟化酶（PHD）酶和缺氧诱导因子（HIF）已被确定为氧敏感机制的关键要素，低氧预处理保护免受伤害的机制仍不清楚。在这里，我们进行血清代谢分析，以评估两个有效的细胞保护方法，缺氧预处理和药理PHD抑制诱导的变化。我们发现这两种方法都增加了血清犬尿氨酸水平并增强了犬尿氨酸生物转化，从而导致缺血后肾脏中NAD+的保留。此外，我们表明，吲哚胺2，3-双加氧酶1（Ido 1）缺乏废除犬尿氨酸的系统性增加和随后的肾保护产生的缺氧预处理和PHD抑制。重要的是，外源性给予犬尿氨酸在Ido 1缺乏的情况下恢复低氧预处理。总的来说，我们的研究结果表明IDO 1-犬尿氨酸轴在介导低氧预适应中的关键作用。Torosyan等人表明，两种有效的细胞保护策略，低氧预处理和PHD抑制，通过激活犬尿氨酸代谢途径增强肾组织对缺血性损伤的恢复力。具体而言，它们促进全身性犬尿氨酸增加并增强犬尿氨酸代谢，导致缺血后肾脏中NAD+的保存和犬尿烯酸的产生。
Prolonged cellular hypoxia leads to energetic failure and death. However, sublethal hypoxia can trigger an adaptive response called hypoxic preconditioning. While prolyl-hydroxylase (PHD) enzymes and hypoxia-inducible factors (HIFs) have been identified as key elements of oxygen-sensing machinery, the mechanisms by which hypoxic preconditioning protects against insults remain unclear. Here, we perform serum metabolomic profiling to assess alterations induced by two potent cytoprotective approaches, hypoxic preconditioning and pharmacologic PHD inhibition. We discover that both approaches increase serum kynurenine levels and enhance kynurenine biotransformation, leading to preservation of NAD+ in the post-ischemic kidney. Furthermore, we show that indoleamine 2,3-dioxygenase 1 (Ido1) deficiency abolishes the systemic increase of kynurenine and the subsequent renoprotection generated by hypoxic preconditioning and PHD inhibition. Importantly, exogenous administration of kynurenine restores the hypoxic preconditioning in the context of Ido1 deficiency. Collectively, our findings demonstrate a critical role of the IDO1-kynurenine axis in mediating hypoxic preconditioning. Torosyan et al. show that two potent cytoprotective strategies, hypoxic preconditioning and PHD inhibition, enhance kidney tissue resilience against ischemic injury by activating the kynurenine metabolic pathway. Specifically, they promote systemic kynurenine increase and enhance kynurenine metabolism, leading to preservation of NAD+ and generation of kynurenic acid in the post-ischemic kidney.
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DOI：
10.4049/jimmunol.1500277
发表时间：
2015-06-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
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
通讯作者：
McGaha TL
DOI：
10.1177/1178646920978236
发表时间：
2020
期刊：
International journal of tryptophan research : IJTR
影响因子：
--
作者：
Kartika R;Wibowo H;Purnamasari D;Pradipta S;Larasati RA
通讯作者：
Larasati RA
影响因子：
13.6
作者：
Hill, Peter;Shukla, Deepa;Maxwell, Patrick H.
通讯作者：
Maxwell, Patrick H.
影响因子：
13.6
作者：
Bernhardt, Wanja M.;Campean, Valentina;Eckardt, Kai-Uwe
通讯作者：
Eckardt, Kai-Uwe
DOI：
10.1073/pnas.1517820112
发表时间：
2015-10-20
影响因子：
11.1
作者：
Cole, Jennifer E.;Astola, Nagore;Monaco, Claudia
通讯作者：
Monaco, Claudia