Abstract: SA-PO227
TBX2 Is a CKD-MBD Causal Gene by Regulating Calcium Homeostasis and Inflammation
Session Information
- CKD-MBD: Basic and Translational
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Bone and Mineral Metabolism
- 501 Bone and Mineral Metabolism: Basic
Authors
- Li, Shen, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Background
Chronic kidney disease–mineral and bone disorder (CKD-MBD) is a syndrome characterized by biochemical mineral abnormalities, bone fragility, and vascular calcification, leading to increased morbidity and mortality. Genome-wide association studies (GWAS) have identified numerous loci associated with kidney diseases. However, the causal variants, genes, cell types, and disease mechanisms remain largely unknown.
Methods
We integrated GWAS, human kidney expression of quantitative trait analysis using Bayesian colocations, and summary-based Mendelian randomization studies to identify likely causal genes for CKD-MBD. We used single-cell RNA data to pinpoint causal cell types. Additionally, we generated TBX2 knockdown (KD) mice to study mechanism.
Results
We prioritized TBX2 (T-Box Transcription Factor 2) as a CKD-MBD risk gene. Human kidney single-cell epigenetic and immunostaining studies indicated kidney connecting tubular cells and vascular smooth muscle cells (VSMCs) as key disease-causing cell types. TBX2-KD mice exhibited increased urinary calcium excretion at baseline and showed heightened susceptibility to kidney injury in a chronic kidney disease model. These mice also demonstrated elevated tissue calcification, leading to activation of crystal-induced NLRP3 inflammasome pathways and increased inflammation.
Conclusion
In summary, our GWAS identified TBX2 as a risk gene for CKD-MBD. We showed that TBX2 regulates tissue calcification and crystal-induced inflammation, thereby influencing CKD-MBD risk and uncovering a novel mechanism for CKD-MBD development.