TRIB3 mediates vascular calcification by facilitating self-ubiquitination and dissociation of Smurf1 in chronic kidney disease
Yihui Li, … , Hao Wang, Ming Zhong
Yihui Li, … , Hao Wang, Ming Zhong
Published February 11, 2025
Citation Information: J Clin Invest. 2025;135(7):e175972. https://doi.org/10.1172/JCI175972.
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TRIB3 mediates vascular calcification by facilitating self-ubiquitination and dissociation of Smurf1 in chronic kidney disease

Abstract

The osteogenic environment promotes vascular calcium phosphate deposition and aggregation of unfolded and misfolded proteins, resulting in ER stress in chronic kidney disease (CKD). Controlling ER stress through genetic intervention is a promising approach for treating vascular calcification. In this study, we demonstrated a positive correlation between ER stress–induced tribble homolog 3 (TRIB3) expression and progression of vascular calcification in human and rodent CKD. Increased TRIB3 expression promoted vascular smooth muscle cell (VSMC) calcification by interacting with the C2 domain of the E3 ubiquitin-protein ligase Smurf1, facilitating its K48-related self-ubiquitination at Lys381 and Lys383 and subsequent dissociation from the plasma membrane and nuclei. This degeneration of Smurf1 accelerated the stabilization of the osteogenic transcription factors RUNX family transcription factor 2 (Runx2) and SMAD family member 1 (Smad1). C/EBP homologous protein and activating transcription factor 4 are upstream transcription factors of TRIB3 in an osteogenic environment. Genetic KO of TRIB3 or rescue of Smurf1 ameliorated VSMC and vascular calcification by stabilizing Smurf1 and enhancing the degradation of Runx2 and Smad1. Our findings shed light on the vital role of TRIB3 as a scaffold in ER stress and vascular calcification and offer a potential therapeutic option for CKD.

Authors

Yihui Li, Chang Ma, Yanan Sheng, Shanying Huang, Huaibing Sun, Yun Ti, Zhihao Wang, Feng Wang, Fangfang Chen, Chen Li, Haipeng Guo, Mengxiong Tang, Fangqiang Song, Hao Wang, Ming Zhong

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Figure 8

Effect of TRIB3 deficiency during metabolic CKD-induced vascular calcification in mice.

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Effect of TRIB3 deficiency during metabolic CKD-induced vascular calcifi...
(A) Representative alizarin red staining of whole aorta images, alizarin red staining of aortic valve sections, and Von Kossa staining of aortic valve sections in metabolic CKD mice. Scale bar: 100 μm. Calcified areas are shown with red staining. (B) Calcium content analysis in the aortic arch of metabolic CKD mice, normalized by dry weight. (C) The area ratio of calcification to the whole aortic area in metabolic CKD mice. Statistical analyses were performed using 2-way ANOVA. (D) The ratio of alizarin red–positive and Von Kossa–positive area to the whole aortic valves (sections with max valve plaque lesion area). Statistical analyses were performed using 2-way ANOVA. (E) PWV in metabolic CKD mice. Statistical analyses were performed using 2-way ANOVA. (F) Representative immunofluorescence of TRIB3, Smurf1, Runx2, and Smad1 in thoracic aortic tissue of metabolic CKD mice. Scale bar: 50 μm. (G) The quantitative analysis for F (n = 5 incontinuous sections from 10 mice per group). Statistical analyses were performed using 2-way ANOVA. **P < 0.01, ***P < 0.001, statistically significant vs. sham ApoE-KO mice; ††P < 0.01, †††P < 0.001, statistically significant vs. diabetes mellitus. ApoE-KO mice. n = 12 per group unless otherwise indicated. Data are shown in scatter dot plots and as the arithmetic mean ± SEM (AU).