TMAO Induced Kidney Aging by Activating ZBP1-Mediated Necroptosis

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.