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The Murine Choline-Deficient, Ethionine-Supplemented CDE Diet Model of Chronic Liver Injury
Published on: October 21, 2017
Dietary choline, via gut microbe- generated trimethylamine-N- oxide, aggravates chronic kidney disease-induced
Feifei Xie1, Xin Zhen1,2, Zhuoliang Liu1
1The State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Key Laboratory of Organ Failure Research (Ministry of Education), Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Insights
Dietary choline worsens heart problems in chronic kidney disease (CKD) by increasing harmful TMAO levels. This reduces blood vessel growth in the heart, worsening cardiac dysfunction in CKD mice.
Area of Science:
- Cardiovascular Research
- Nephrology
- Microbiome Research
Background:
- Chronic kidney disease (CKD) is a major global health issue linked to increased cardiovascular disease (CVD) risk.
- Trimethylamine-N-oxide (TMAO), a toxin from gut microbes metabolizing choline and carnitine, is associated with CVD events in CKD patients.
- The exact mechanisms by which TMAO contributes to CKD-induced cardiac injury are not fully understood.
Purpose of the Study:
- To investigate the hypothesis that TMAO exacerbates cardiac injury in CKD.
- To explore the underlying mechanisms linking dietary choline, TMAO, and cardiac dysfunction in CKD.
Main Methods:
- A 5/6 nephrectomy model was used to induce CKD in CD1 mice.
- Mice were fed a diet supplemented with choline (1.2%) for 8 weeks.
- Serum TMAO levels, cardiac function, capillary density, gene expression, and Hif-1α protein levels were analyzed.
Main Results:
- CKD mice showed elevated serum TMAO levels, further increased by dietary choline.
- Dietary choline aggravated CKD-induced cardiac dysfunction, which was improved by reducing TMAO levels with medicinal charcoal.
- Choline-treated CKD mice exhibited reduced cardiac capillary density and angiogenesis-related gene expression, along with decreased cardiac Hif-1α protein levels.
- Hif-1α stabilization with FG-4592 improved cardiac angiogenesis and function in choline-fed CKD mice.
Conclusions:
- Dietary choline, through gut microbe-generated TMAO, inhibits cardiac angiogenesis by suppressing Hif-1α protein levels.
- This mechanism exacerbates cardiac dysfunction in the context of CKD.
- Targeting TMAO production or enhancing Hif-1α signaling may offer therapeutic strategies for CKD-related cardiac complications.
Abstract:
Chronic kidney disease (CKD) is a global public health problem that shortens lifespan primarily by increasing the risk of cardiovascular diseases. Trimethylamine-N-oxide (TMAO), a gut microbiota-derived toxin produced by metabolizing high-choline or carnitine foods, is associated with cardiovascular events in patients with CKD. Although the deleterious effect of TMAO on CKD-induced cardiac injury has been confirmed by various researches, the mechanisms remain unclear. Here, we tested the hypothesis that TMAO aggravates CKD-induced cardiac injury and explores the potential mechanism. CD1 mice underwent 5/6 nephrectomy to induce CKD, and then fed with a diet supplemented with choline (1.2% total) for 8 weeks. Serum TMAO levels were elevated in CKD mice compared with SHAM group, and higher TMAO levels were found in choline-supplemented CKD mice compared with CKD group. Dietary choline aggravated CKD-induced cardiac dysfunction, and reducing TMAO levels via medicinal charcoal tablets improved cardiac dysfunction. RNA-seq analysis revealed that dietary choline affected cardiac angiogenesis in CKD mice. Reduced cardiac capillary density and expressions of angiogenesis-related genes were observed in choline-treated CKD mice. Furthermore, dietary choline inhibited cardiac Hif-1α protein level in CKD mice, and Hif-1α stabilizer FG-4592 could improve cardiac angiogenesis and dysfunction in CKD mice on a high-choline diet. In conclusion, these data indicate that dietary choline, via gut microbe-generated TMAO, inhibits cardiac angiogenesis by reducing Hif-1α protein level, ultimately aggravates cardiac dysfunction in CKD mice.
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