Contribution of multidrug and toxin extrusion protein 1 (MATE1) to renal secretion of trimethylamine-N-oxide (TMAO)

Gessner, Arne; König, Jörg; Fromm, MF

doi:10.1038/s41598-018-25139-8

Cited by 21 publications

(24 citation statements)

References 44 publications

(89 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Yet, we did not find a significant correlation between plasma levels of TMAO and total protein intake. Moreover, several studies in animal or cellular models have shown involvement of tubular transporters such as organic cation transporter 2 (OCT2) in TMAO cellular uptake and efflux [23,24,25]. This, however, has not been confirmed in humans unlike what has been previously described for creatinine [25].…”

Section: Discussionmentioning

confidence: 99%

Elevation of Trimethylamine-N-Oxide in Chronic Kidney Disease: Contribution of Decreased Glomerular Filtration Rate

Pelletier

Croyal²,

Ene

et al. 2019

Toxins

View full text Add to dashboard Cite

Gut microbiota-dependent Trimethylamine-N-oxide (TMAO) has been reported to be strongly linked to renal function and to increased cardiovascular events in the general population and in Chronic Kidney Disease (CKD) patients. Considering the lack of data assessing renal handling of TMAO, we conducted this study to explore renal excretion and mechanisms of accumulation of TMAO during CKD. We prospectively measured glomerular filtration rate (mGFR) with gold standard methods and plasma concentrations of trimethylamine (TMA), TMAO, choline, betaine, and carnitine by LC-MS/MS in 124 controls, CKD, and hemodialysis (HD) patients. Renal clearance of each metabolite was assessed in a sub-group of 32 patients. Plasma TMAO was inversely correlated with mGFR (r2 = 0.388, p < 0.001), confirming elevation of TMAO plasma levels in CKD. TMAO clearances were not significantly different from mGFR, with a mean ± SD TMAO fractional excretion of 105% ± 32%. This suggests a complete renal excretion of TMAO by glomerular filtration with a negligible participation of tubular secretion or reabsorption, during all stages of CKD. Moreover, TMAO was effectively removed within 4 h of hemodiafiltration, showing a higher fractional reduction value than that of urea (84.9% ± 6.5% vs. 79.2% ± 5.7%, p = 0.04). This study reports a strong correlation between plasma TMAO levels and mGFR, in CKD, that can be mainly related to a decrease in TMAO glomerular filtration. Clearance data did not support a significant role for tubular secretion in TMAO renal elimination.

show abstract

Section: Discussionmentioning

confidence: 99%

Elevation of Trimethylamine-N-Oxide in Chronic Kidney Disease: Contribution of Decreased Glomerular Filtration Rate

Pelletier

Croyal²,

Ene

et al. 2019

Toxins

View full text Add to dashboard Cite

show abstract

“…TMAO is eventually cleared mainly by the kidneys, excreted in urine in part through tubular cell secretion involving uptake by organic cation transporters (OCTs) OCT1 and OCT2 as well as transporters of the ATP-binding cassette (ABC) family, including ABCG2 (BCRP) and ABCB1 (MDR1) [ 71 , 72 ]. Multidrug and toxin extrusion protein 1 (MATE1) contributes to translocation of TMAO across the luminal membrane of proximal tubular cells [ 73 ]. Indeed, genetic ABCG2 variants modulate TMAO exposure in humans [ 72 ].…”

Section: Metabolite Overload: Microbiota-generated Nephrotoxinsmentioning

confidence: 99%

Impact of Altered Intestinal Microbiota on Chronic Kidney Disease Progression

Castillo-Rodríguez

Fernández-Prado

Esteras

et al. 2018

Toxins

117

View full text Add to dashboard Cite

In chronic kidney disease (CKD), accumulation of uremic toxins is associated with an increased risk of CKD progression. Some uremic toxins result from nutrient processing by gut microbiota, yielding precursors of uremic toxins or uremic toxins themselves, such as trimethylamine N-Oxide (TMAO), p-cresyl sulphate, indoxyl sulphate and indole-3 acetic acid. Increased intake of some nutrients may modify the gut microbiota, increasing the number of bacteria that process them to yield uremic toxins. Circulating levels of nutrient-derived uremic toxins are associated to increased risk of CKD progression. This offers the opportunity for therapeutic intervention by either modifying the diet, modifying the microbiota, decreasing uremic toxin production by microbiota, increasing toxin excretion or targeting specific uremic toxins. We now review the link between nutrients, microbiota and uremic toxin with CKD progression. Specific focus will be placed on the generation specific uremic toxins with nephrotoxic potential, the decreased availability of bacteria-derived metabolites with nephroprotective potential, such as vitamin K and butyrate and the cellular and molecular mechanisms linking these toxins and protective factors to kidney diseases. This information provides a conceptual framework that allows the development of novel therapeutic approaches.

show abstract

“…In healthy subjects, TMAO is efficiently excreted in the urine to maintain serum levels below about 10 μM [ 60 , 71 , 129 , 138 ]. Glomerular filtration and uptake by proximal tubular cells through organic cation transport proteins regulates circulating TMAO and prevents excess accumulation [ 133 , 139 , 140 ]. While small amounts may be secreted as TMA after retroconversion, renal FMO3 and 1 expression accounts for over 96% being excreted as TMAO [ 128 , 129 , 141 , 142 ].…”

Section: Tmao Accumulation In Serummentioning

confidence: 99%

The Accumulation and Molecular Effects of Trimethylamine N-Oxide on Metabolic Tissues: It’s Not All Bad

2021

View full text Add to dashboard Cite

Since elevated serum levels of trimethylamine N-oxide (TMAO) were first associated with increased risk of cardiovascular disease (CVD), TMAO research among chronic diseases has grown exponentially. We now know that serum TMAO accumulation begins with dietary choline metabolism across the microbiome-liver-kidney axis, which is typically dysregulated during pathogenesis. While CVD research links TMAO to atherosclerotic mechanisms in vascular tissue, its molecular effects on metabolic tissues are unclear. Here we report the current standing of TMAO research in metabolic disease contexts across relevant tissues including the liver, kidney, brain, adipose, and muscle. Since poor blood glucose management is a hallmark of metabolic diseases, we also explore the variable TMAO effects on insulin resistance and insulin production. Among metabolic tissues, hepatic TMAO research is the most common, whereas its effects on other tissues including the insulin producing pancreatic β-cells are largely unexplored. Studies on diseases including obesity, diabetes, liver diseases, chronic kidney disease, and cognitive diseases reveal that TMAO effects are unique under pathologic conditions compared to healthy controls. We conclude that molecular TMAO effects are highly context-dependent and call for further research to clarify the deleterious and beneficial molecular effects observed in metabolic disease research.

show abstract

Contribution of multidrug and toxin extrusion protein 1 (MATE1) to renal secretion of trimethylamine-N-oxide (TMAO)

Cited by 21 publications

References 44 publications

Elevation of Trimethylamine-N-Oxide in Chronic Kidney Disease: Contribution of Decreased Glomerular Filtration Rate

Elevation of Trimethylamine-N-Oxide in Chronic Kidney Disease: Contribution of Decreased Glomerular Filtration Rate

Impact of Altered Intestinal Microbiota on Chronic Kidney Disease Progression

The Accumulation and Molecular Effects of Trimethylamine N-Oxide on Metabolic Tissues: It’s Not All Bad

Contact Info

Product

Resources

About