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黄素单加氧酶 3 缺乏可保护小鼠缺血再灌注后的肾功能。

Deficiency of flavin-containing monooxygenase 3 protects kidney function after ischemia-reperfusion in mice.

机构信息

Department of Anaesthesiology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.

Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.

出版信息

Commun Biol. 2024 Aug 27;7(1):1054. doi: 10.1038/s42003-024-06718-0.

DOI:10.1038/s42003-024-06718-0
PMID:39191965
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11350001/
Abstract

The kidney is vulnerable to ischemia and reperfusion (I/R) injury that can be fatal after major surgery. Currently, there are no effective treatments for I/R-induced kidney injury. Trimethylamine N-oxide (TMAO) is a gut-derived metabolite linked to many diseases, but its role in I/R-induced kidney injury remains unclear. Here, our clinical data reveals an association between preoperative systemic TMAO levels and postoperative kidney injury in patients after post-cardiopulmonary bypass surgery. By genetic deletion of TMAO-producing enzyme flavin-containing monooxygenase 3 (FMO3) and dietary supplementation of choline to modulate TMAO levels, we found that TMAO aggravated acute kidney injury through the triggering of endoplasmic reticulum (ER) stress and worsened subsequent renal fibrosis through TGFβ/Smad signaling activation. Together, our study underscores the negative role of TMAO in I/R-induced kidney injury and highlights the therapeutic potential through the modulation of TMAO levels by targeting FMO3, thereby mitigating acute kidney injury and preventing subsequent renal fibrosis.

摘要

肾脏容易受到缺血再灌注（I/R）损伤的影响，这种损伤在大手术后可能是致命的。目前，对于 I/R 引起的肾损伤还没有有效的治疗方法。三甲胺 N-氧化物（TMAO）是一种与许多疾病相关的肠道衍生代谢物，但它在 I/R 引起的肾损伤中的作用尚不清楚。在这里，我们的临床数据显示，体外循环后心脏手术后患者术前全身 TMAO 水平与术后肾损伤之间存在关联。通过基因敲除 TMAO 产生酶黄素单加氧酶 3（FMO3）和饮食补充胆碱来调节 TMAO 水平，我们发现 TMAO 通过触发内质网（ER）应激加重急性肾损伤，并通过 TGFβ/Smad 信号通路激活加重随后的肾纤维化。总之，我们的研究强调了 TMAO 在 I/R 引起的肾损伤中的负面作用，并通过靶向 FMO3 来调节 TMAO 水平来突出其治疗潜力，从而减轻急性肾损伤并防止随后的肾纤维化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bd1a/11350001/9d161e29afae/42003_2024_6718_Fig7_HTML.jpg
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