Abstract
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.
Highlights
Trimethylamine N-oxide (TMAO) is the result of the oxidation of trimethylamine (TMA) primarily by the enzyme flavin-containing monooxygenase 3 in the liver
Detection of myofibroblasts in histopathologic kidney samples is a prognostic index for fibrosis progression and progression of tubular atrophy [20]
We found that the expression of α-SMA was increased in renal fibroblasts after treatment with TMAO for 24 h compared to unstimulated cells, as detected with immunofluorescence and Western blot (Figure 1A,B)
Summary
Trimethylamine N-oxide (TMAO) is the result of the oxidation of trimethylamine (TMA) primarily by the enzyme flavin-containing monooxygenase 3 in the liver. It can be generated by the oxidation of TMA that takes place in the gut microbiota [1]. TMA is produced by gut residing microbes using diet compounds such as choline, betaine, L-carnitine, ergothioneine, and gamma-butyrobetaine as precursors. These precursors are mainly obtained from dairy products, fish, shrimp, red meat, wheat, and beans. TMAO has a variety of properties in order to facilitate the homeostasis of organisms. TMAO is an electron acceptor during the anaerobic metabolism of Enterobacteriaceae, which are bacteria of the human gut flora [4]
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