TMAO regulates renal tubular epithelial cell senescence through circVmn2r1
Year: 2026
Type: article
Abstract: The gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) is an established risk factor for cardiovascular and renal diseases, yet its role in driving kidney aging remains poorly defined. Circular RNAs (circRNAs) have emerged as critical regulators of cellular senescence, but their integration with systemic metabolic cues in aging processes is largely unknown. Here, we identify a novel signaling axis through which TMAO accelerates renal senescence by dysregulating a specific circRNA pathway. We demonstrate that TMAO treatment induces a senescent phenotype in renal tubular epithelial cells and promotes kidney aging in mice, as evidenced by increased senescence-associated β-galactosidase activity and elevated expression of p53, p21, and p16. Mechanistically, TMAO significantly upregulates the expression of circVmn2r1, a circRNA we previously identified as a key promoter of kidney aging. This upregulation triggers the activation of the the nucleotide-binding domain, leucine-rich repeat-containing family, pyrin domain-containing 3 (NLRP3) inflammasome, leading to increased caspase-1 cleavage and elevated levels of the pro-inflammatory cytokines pro-IL-1β and pro-IL-18. Crucially, genetic knockdown of circVmn2r1 in vitro and in vivo significantly attenuates TMAO-induced NLRP3 upregulation, inflammasome activation, and cellular senescence. Our findings reveal that TMAO functions as an upstream metabolic trigger that promotes renal aging via the circVmn2r1/NLRP3 inflammasome axis. This study elucidates a direct link between a diet-derived metabolite and a specific circRNA-mediated pro-aging pathway, identifying circVmn2r1 as a potential therapeutic target for mitigating metabolic stress-induced kidney aging.
Source: Renal Failure
Language: English
Topic: Circular RNAs in diseases
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,306
OpenAlex ID: W7225613693