TMAO Induced Kidney Aging by Activating ZBP1-Mediated Necroptosis

The present study was aimed to investigate whether trimethylamine-N-oxide (TMAO) contributed to kidney aging by activating necroptosis. Male C57BL/6J mice were randomly divided into Control group (3 months old) and Old group (18 months old), compared to 3-month-old controls, 18-month-old male C57BL/6J mice showed significant increases in plasma creatinine (Cre) and blood urea nitrogen (BUN) ( P <0.05), enhanced renal fibrosis ( P <0.001), elevated plasma TMAO ( P <0.01), and upregulation of senescence markers p53, p21, and p16 ( P <0.05, P <0.01, and P <0.001, respectively). In order to investigate the effects of TMAO on kidney aging, the mice were intraperitoneally injected with TMAO for one to three months, mice showed time-dependent increases in Cre and BUN ( P <0.05, respectively), progressive fibrosis, and gradual upregulation of senescence markers, ZBP1, and phosphorylation of RIPK3 and MLKL ( P <0.05, respectively). In addition, three months of DMB treatment (inhibitor for TMAO formation) significantly reduced the plasma Cre and BUN levels ( P <0.001 and P <0.05), downregulated the senescence markers expression, and improved kidney fibrosis ( P <0.001 or P <0.05, respectively). In conclusion, our studies revealed that TMAO induced kidney aging by activating ZBP1-mediated necroptosis. Moreover, the inhibition of TMAO generation might be a potential treatment for kidney aging.