Inhibition of microbiota-dependent TMAO production attenuates chronic kidney disease in mice

Zhang, Wenchao; Miikeda, Aika; Zuckerman, Jonathan E.; Jia, Xun; Charugundla, Sarada; Zhou, Zhiqiang; Kaczor‐Urbanowicz, Karolina Elżbieta; Magyar, Clara E.; Guo, Fangfei; Wang, Zeneng; Pellegrini, Matteo; Hazen, Stanley L.; Nicholas, Susanne B.; Lusis, Aldons J.; Shih, Diana M.

doi:10.1038/s41598-020-80063-0

Cited by 79 publications

(61 citation statements)

References 63 publications

(95 reference statements)

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“…Moreover, the TMAO inhibitor 3,3-dimethyl-1-butanol (DMB) can inhibit the TGF-β 1 /Smad3 pathway by reducing TMAO levels, thereby alleviating cardiac fibrosis in mice ( Wang et al, 2020 ). Iodomethylcholine can inhibit the progression of adenine-induced CKD in mice by inhibiting TMAO levels and reducing collagen deposition ( Zhang et al, 2021 ), and it can also inhibit the expression of pro-fibrotic genes, such as those encoding for TGF-β, type I collagen, tissue inhibitor of metalloproteinase 1, and α-SMA, to alleviate renal tubular interstitial fibrosis and dysfunction in CKD mice ( Gupta et al, 2020 ). In this study, the Masson staining results directly showed renal interstitial fibrosis in the rats with DKD, and the degree of renal interstitial fibrosis in the DKD + TMAO group was further aggravated.…”

Section: Discussionmentioning

confidence: 99%

Trimethylamine N-Oxide Exacerbates Renal Inflammation and Fibrosis in Rats With Diabetic Kidney Disease

et al. 2021

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The gut microbiota plays a pivotal role in the onset and development of diabetes and its complications. Trimethylamine N-oxide (TMAO), a gut microbiota-dependent metabolite of certain nutrients, is associated with type 2 diabetes and its complications. Diabetic kidney disease (DKD) is one of the most serious microvascular complications. However, whether TMAO accelerates the development of DKD remains unclear. We tested the hypothesis that TMAO accelerates the development of DKD. A high-fat diet/low-dose streptozotocin-induced diabetes rat model was established, with or without TMAO in the rats’ drinking water. Compared to the normal rats, the DKD rats showed significantly higher plasma TMAO levels at the end of the study. TMAO treatment not only exacerbated the kidney dysfunction of the DKD rats, but also renal fibrosis. Furthermore, TMAO treatment activated the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome and resulted in the release of interleukin (IL)-1β and IL-18 to accelerate renal inflammation. These results suggested that TMAO aggravated renal inflammation and fibrosis in the DKD rats, which provides a new perspective to understand the pathogenesis of DKD and a potential novel target for preventing the progression of DKD.

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Section: Discussionmentioning

confidence: 99%

Trimethylamine N-Oxide Exacerbates Renal Inflammation and Fibrosis in Rats With Diabetic Kidney Disease

et al. 2021

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“…Activation of Smad3 by TGF-β1 leads to nuclear translocation of Smad3 to activate hypertrophic and pro-fibrotic genes, causing cardiac and renal interstitial fibrosis and myocyte hypertrophy ( Pan et al, 2020 ). TMAO has been reported to promote cardiac remodeling and renal interstitial fibrosis by activating NF-kB and Smad3 ( Tang et al, 2015 ; Yu et al, 2018 ; Li Z. et al, 2019 ; Zhang et al, 2021 ), whereas inhibition of TMAO reduces activation of NF-kB and Smad3, preventing cardiac remodeling and renal interstitial fibrosis in multiple cardiac and renal diseases ( Li Z. et al, 2019 ; Zhang et al, 2021 ). Thus, inhibition of TMAO prevents the progression of cardiac and renal dysfunction in CRS2 rats probably by suppressing activation of NF-kB and Smad3 signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Attenuation of Circulating Trimethylamine N-Oxide Prevents the Progression of Cardiac and Renal Dysfunction in a Rat Model of Chronic Cardiorenal Syndrome

Zou

Sun

2021

Front. Pharmacol.

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Chronic heart failure (HF) frequently causes progressive decline in kidney function, known as cardiorenal syndrome-2 (CRS2). Current treatment options for CRS2 remain unacceptably limited. Trimethylamine-N-oxide (TMAO), a metabolite of gut microbiota, has recently been implicated in the pathogenesis of both HF and chronic kidney disease. Here we examined whether circulating TMAO is elevated in CRS2 and if so, whether attenuation of circulating TMAO would ameliorate the progression of CRS2. Sprague-Dawley rats underwent surgery for myocardial infarction (MI) or sham (week 0) followed by subtotal (5/6) nephrectomy (STNx) or sham at week 4 to induce CRS2 or control. At week 6, MI + STNx rats and control rats received vehicle or 1.0% 3,3-Dimethyl-1-butanol (DMB, a TMAO inhibitor) treatment for 8 weeks. Compared with control rats, MI + STNx rats exhibited elevated serum TMAO at week 6, which was increased further at week 14 but was attenuated by DMB treatment. MI + STNx rats showed cardiac dysfunction as assessed by echocardiography and renal dysfunction as evidenced by increased serum creatinine and urinary kidney injury molecule-1 and decreased creatinine clearance at week 6. The cardiac and renal dysfunction in MI + STNx rats was exacerbated at week 14 but was prevented by DMB treatment. Molecular and histological studies revealed myocyte hypertrophy and increases in interstitial myocardial fibrosis and gene expression of pro-hypertrophic and pro-fibrotic markers in both heart and kidney at week 14, which were accompanied by elevated gene expression of proinflammatory cytokines. The changes in molecular and histological parameters observed in MI + STNx rats were significantly reduced by DMB treatment. These findings suggest that rats with CRS2 have elevated circulating TMAO, which is associated with the exacerbation of cardiac and renal dysfunction. Attenuation of circulating TMAO can ameliorate cardiac and renal injury and prevents the progression of CRS2.

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“…Elevated plasma levels of TMAO are associated with a poor prognosis in CKD patients [17], higher incidence of hospitalizations in hemodialysis patients [18], and reduced survival [13]. A CKD mouse model fed iodomethylcholine, an indirect TMAO inhibitor that suppresses TMA generation, exhibited reduced levels of renal injury markers such as urea, fibroblast growth factor 23 (FGF23), and cystatin C [19]. The latter marker of functional impairment was also increased in TMAO-fed mice.…”

Section: Introductionmentioning

confidence: 99%

The Fibrotic Effects of TMAO on Human Renal Fibroblasts Is Mediated by NLRP3, Caspase-1 and the PERK/Akt/mTOR Pathway

Kapetanaki

Kumawat

Persson

et al. 2021

IJMS

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Trimethylamine N-oxide (TMAO), a product of gut microbiota metabolism, has previously been shown to be implicated in chronic kidney disease. A high TMAO-containing diet has been found to cause tubulointerstitial renal fibrosis in mice. However, today there are no data linking specific molecular pathways with the effect of TMAO on human renal fibrosis. The aim of this study was to investigate the fibrotic effects of TMAO on renal fibroblasts and to elucidate the molecular pathways involved. We found that TMAO promoted renal fibroblast activation and fibroblast proliferation via the PERK/Akt/mTOR pathway, NLRP3, and caspase-1 signaling. We also found that TMAO increased the total collagen production from renal fibroblasts via the PERK/Akt/mTOR pathway. However, TMAO did not induce fibronectin or TGF-β1 release from renal fibroblasts. We have unraveled that the PERK/Akt/mTOR pathway, NLRP3, and caspase-1 mediates TMAO’s fibrotic effect on human renal fibroblasts. Our results can pave the way for future research to further clarify the molecular mechanism behind TMAO’s effects and to identify novel therapeutic targets in the context of chronic kidney disease.

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Inhibition of microbiota-dependent TMAO production attenuates chronic kidney disease in mice

Cited by 79 publications

References 63 publications

Trimethylamine N-Oxide Exacerbates Renal Inflammation and Fibrosis in Rats With Diabetic Kidney Disease

Trimethylamine N-Oxide Exacerbates Renal Inflammation and Fibrosis in Rats With Diabetic Kidney Disease

Attenuation of Circulating Trimethylamine N-Oxide Prevents the Progression of Cardiac and Renal Dysfunction in a Rat Model of Chronic Cardiorenal Syndrome

The Fibrotic Effects of TMAO on Human Renal Fibroblasts Is Mediated by NLRP3, Caspase-1 and the PERK/Akt/mTOR Pathway

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