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Figure 1From Scientific Reports · CC BY-NC-ND
Animals

TMEM174 deficiency shortens lifespan and stiffens vessels in mice

Knocking out the proximal tubule protein in mice shortened survival, whereas altering dietary phosphate intake regulated vascular calcification, stiffness, and mortality.

Scientific Reports

In mice, deficiency of the renal proximal tubule protein TMEM174 significantly shortened lifespan compared to wild-type controls. Researchers evaluated TMEM174 knockout mice across C57BL6/J and DBA/2 J genetic backgrounds fed diets containing either 0.6% or 1.2% phosphate. The high-phosphate diet exacerbated vascular calcification, vascular stiffness, and mortality, while the low-phosphate diet rescued these phenotypes. Additional experiments in cultured OKP cells showed that TMEM174 regulates the phosphate co-transporter NPT2A. Silencing TMEM174 blocked parathyroid hormone-induced NPT2A endocytosis, retaining the transporter at the apical cell membrane. The authors found that the C-terminal domain of TMEM174 is essential for binding and degrading NPT2A, whereas C-terminal deletion mutants failed to interact with or clear the protein.

Why it matters

Disrupted phosphate balance contributes to vascular disease and reduced longevity in both chronic kidney disease and aging. Uncovering TMEM174 as a key regulator of renal phosphate excretion identifies a potential mechanistic target to curb phosphate-driven cardiovascular decline.

Caveats

The findings are limited to mouse models and cultured opossum kidney cells, so their translation to human renal physiology remains unverified. The abstract also does not quantify the specific magnitude of lifespan reduction in the knockout mice.

The paper

TMEM174 deficiency reduces longevity by promoting phosphate-driven vascular calcification

Miranda JG, Blaine J, Miyazaki M

Scientific Reports · 2 Oct 2026

doi.org/10.1038/s41598-026-74353-2

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