1. Deficiency of flavin-containing monooxygenase 3 protects kidney function after ischemia-reperfusion in mice.
- Author
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Wang J, Wang W, Zhang J, Xiao F, Li Z, Xu P, Wang H, Du H, Liu S, Li H, Zhang X, Chen S, Gao Z, Wang S, Wang J, and Song M
- Subjects
- Animals, Mice, Male, Mice, Knockout, Mice, Inbred C57BL, Humans, Fibrosis, Signal Transduction, Endoplasmic Reticulum Stress, Transforming Growth Factor beta metabolism, Reperfusion Injury metabolism, Oxygenases metabolism, Oxygenases genetics, Methylamines metabolism, Kidney metabolism, Kidney pathology, Acute Kidney Injury metabolism, Acute Kidney Injury etiology, Acute Kidney Injury prevention & control
- 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., (© 2024. The Author(s).)
- Published
- 2024
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