Trimethylamine-N-Oxide Aggravates Kidney Injury via Activation of p38/MAPK Signaling and Upregulation of HuR

Yunshi Lai, Haie Tang, Xinrong Zhang, Zhanmei Zhou, Miaomiao Zhou, Zheng Hu, Fengxin Zhu, Lei Zhang, Jing Nie
2021 Kidney & Blood Pressure Research  
<b><i>Background:</i></b> Trimethylamine-N-oxide (TMAO) is an intestinal metabolic toxin, which is produced by gut flora via metabolizing high-choline foods. TMAO is known to increase the risk of atherosclerosis and cardiovascular events in chronic kidney disease (CKD) patients. <b><i>Objectives:</i></b> The objective of this study was to explore the role and mechanism of TMAO aggravating kidney injury. <b><i>Method:</i></b> We used the five-sixths nephrectomy (5/6 Nx)-induced CKD rats to
more » ... igate whether TMAO could aggravate kidney damage and its possible mechanisms. Six weeks after the operation, the two groups of 5/6 Nx rats were subjected to intraperitoneal injection with 2.5% glucose peritoneal dialysis fluid (2.5% PDF) and 2.5% PDF plus TMAO 20 mg/kg/day. <b><i>Results:</i></b> In this study, we provided evidence showing TMAO significantly aggravated renal failure as well as inflammatory cell infiltration and in five-sixths nephrectomy-induced CKD rats. We found that TMAO could upregulate inflammatory factors including MCP-1, TNF-α, IL-6, IL-1β, and IL-18 by activating p38 phosphorylation and upregulation of human antigen R. TMAO could aggravate oxidative stress by upregulating NOX4 and downregulating SOD. The result also confirmed that TMAO promoted NLRP3 inflammasome formation as well as cleaved caspase-1 and IL-1β activation in the kidney tissue. <b><i>Conclusions:</i></b> Taken together, the present study validates TMAO as a pro-inflammatory factor that causes renal inflammatory injury and renal function impairment. Inhibition of TMAO synthesis or promoting its clearance may be a potential therapeutic approach of CKD in the future.
doi:10.1159/000519603 pmid:34788763 fatcat:ssuoft23jzhg7o4gxk73szxiey