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TMAO Induced Kidney Aging by Activating ZBP1-Mediated Necroptosis
1Department of Clinical Diagnostics, Hebei Medical University, Shijiazhuang, 050017, China. 18201400@hebmu.edu.cn; Department of Pharmacy, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Pudong, Shanghai, China. mafenfen2005@126.com.
Abstract:
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. Key words Kidney aging " Trimethylamine-N-oxide " ZBP1 " Necroptosis " DMB.
Insights
Trimethylamine-N-oxide (TMAO) accelerates kidney aging by activating ZBP1-mediated necroptosis. Inhibiting TMAO formation may offer a potential therapeutic strategy for age-related kidney decline.
Area of Science:
- Gerontology and Nephrology: Investigating the molecular mechanisms of kidney aging.
Background:
- Aging is associated with increased kidney dysfunction, characterized by elevated creatinine and blood urea nitrogen.
- Trimethylamine-N-oxide (TMAO) levels are elevated in aged kidneys, suggesting a potential role in the aging process.
Purpose of the Study:
- To determine if TMAO contributes to kidney aging by activating necroptosis.
- To explore the potential of inhibiting TMAO formation as a therapeutic intervention for kidney aging.
Main Methods:
- Comparison of kidney function, fibrosis, TMAO levels, and senescence markers in young (3-month-old) and old (18-month-old) male C57BL/6J mice.
- Intraperitoneal injection of TMAO in mice to assess its direct effects on kidney aging markers.
- Treatment with DMB, an inhibitor of TMAO formation, to evaluate its renoprotective effects.
Main Results:
- Old mice exhibited significantly higher plasma creatinine, blood urea nitrogen, renal fibrosis, plasma TMAO, and senescence markers compared to young controls.
- TMAO administration induced time-dependent increases in kidney dysfunction markers, fibrosis, senescence, and necroptosis pathway activation (ZBP1, RIPK3, MLKL).
- DMB treatment significantly ameliorated kidney dysfunction, reduced senescence markers, and improved renal fibrosis, indicating TMAO's detrimental role.
Conclusions:
- TMAO induces kidney aging by activating ZBP1-mediated necroptosis.
- Inhibiting TMAO generation presents a promising therapeutic avenue for mitigating kidney aging.
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