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Abstract: FR-PO385

The IRE1α/XBP1s Pathway Promotes Vascular Calcification in CKD by Enhancing Oxidative Phosphorylation

Session Information

  • Hypertension and CVD: Basic
    November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

  • 1601 Hypertension and CVD: Basic

Authors

  • He, Fan, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
  • Shi, Jia, The First Affiliated Hospital of Chongqing Medical University, Chongqing, Chongqing, China
  • Wang, Nan Ya, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
  • Xu, Gang, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
  • Li, Qing, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
Background

Endoplasmic reticulum stress has been reported to be linked to several vascular diseases. However, whether Inositol-requiring enzyme 1α (IRE1α) participate in vascular calcification in chronic kidney disease remains poorly understood.

Methods

The expression level of IRE1α were measured in the artery tissues of CKD patients and mice. The Ern1flox/flox mice were intercrossed with SMMHC-CreERT2 to obtain VSMC-specific IRE1α knockout mice (Ern1 flox/flox; SMMHC-Cre). The mice were treated with vitamin D3 to induce vascular calcification. Besides, VSMC were stimulated with high phosphate or human uremic serum to induce calcification.The calcium content and Alizarin red staining were used for analysis of calcification, and the mRNA expression level of IRE1α, XBP1s and regulated IRE1-dependent decay-related genes were measured. After transfected with Ad-XBP1s, transcriptome analysis was performed.

Results

The expression level of IRE1α were upregulated in the artery tissues of CKD patients and mice, and in high phosphate and human uremic serum-stimulated VSMC. Specific knockout of IRE1α in VSMC alleviated vascular calcification both in vivo and ex vivo, and siIRE1α attenuated VSMC calcification in vitro.The mRNA expression level of XBP1s were decreased in the aortic tissues of Ern1 flox/flox; SMMHC-Cre mice, while the expression level of regulated IRE1-dependent decay-related genes remained unchanged. Knockout of IRE1α inhibits high phosphate-induced calcification, which could be reversed by XBP1s overexpression. Overexpression of XBP1s enhanced oxidative phosphorylation of VSMC.

Conclusion

The IRE1α/XBP1s Pathway Promotes Vascular Calcification in Chronic Kidney Disease by Enhancing Oxidative Phosphorylation.

Funding

  • Government Support – Non-U.S.