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Updated: Jun 15, 2025
Ischemia-reperfusion Model of Acute Kidney Injury and Post Injury Fibrosis in Mice
Published on: August 9, 2013
Deficiency of flavin-containing monooxygenase 3 protects kidney function after ischemia-reperfusion in mice
Jiawan Wang1,2, Wei Wang3, Jiandong Zhang4,3
1Department of Anaesthesiology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China. bargitta_wjw@hotmail.com.
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.
Insights
Trimethylamine N-oxide (TMAO) worsens kidney injury after surgery by causing endoplasmic reticulum stress and fibrosis. Targeting TMAO production may offer new treatments for ischemia-reperfusion kidney injury.
Area of Science:
- Nephrology
- Cardiovascular Surgery
- Metabolomics
Background:
- Kidney ischemia-reperfusion (I/R) injury is a critical complication after major surgery, with limited treatment options.
- The role of the gut-derived metabolite trimethylamine N-oxide (TMAO) in I/R-induced kidney injury is not well understood.
Purpose of the Study:
- To investigate the association between preoperative TMAO levels and postoperative kidney injury.
- To elucidate the mechanisms by which TMAO affects I/R-induced kidney injury and subsequent renal fibrosis.
Main Methods:
- Analysis of clinical data correlating preoperative TMAO levels with postoperative kidney injury in patients undergoing cardiopulmonary bypass surgery.
- Experimental models involving genetic deletion of flavin-containing monooxygenase 3 (FMO3), a TMAO-producing enzyme, and dietary choline supplementation to modulate TMAO levels.
- Assessment of endoplasmic reticulum (ER) stress and TGFβ/Smad signaling activation in response to TMAO.
Main Results:
- Preoperative TMAO levels were associated with increased risk of postoperative kidney injury.
- Elevated TMAO aggravated acute kidney injury by triggering ER stress.
- TMAO exacerbated renal fibrosis through activation of the TGFβ/Smad signaling pathway.
Conclusions:
- TMAO plays a detrimental role in ischemia-reperfusion-induced kidney injury and subsequent renal fibrosis.
- Targeting TMAO production, potentially by inhibiting FMO3, represents a promising therapeutic strategy to mitigate kidney injury and prevent fibrosis.
