Abstract: PO0332
A Role of FHL2 in the Pathogenesis of VOT and Calcification Induced by High Phosphate
Session Information
- Bone and Mineral Metabolism: Basic
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Bone and Mineral Metabolism
- 401 Bone and Mineral Metabolism: Basic
Authors
- Huang, Xiaowen, Nanjing Medical University, Nanjing, Jiangsu, China
- He, Weichun, Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
Background
Hyperphosphatemia is germane to the development and progression of arterial medial calcification (AMC) in patients with chronic kidney disease. Vascular smooth muscle cells (VSMCs) to osteoblast-like cells transdifferentiation (VOT) induced by high phosphate is a crucial step in AMC. Either β-catenin or HIF-1α signal activated by high phosphate promotes VOT and calcification in VSMCs. As an adaptor protein, four-and-a-half LIM domains protein 2 (FHL2) has been demonstrated involving in β-catenin and HIF-1α signaling, respectively. However, the potential role and mechanism for FHL2 in high-phosphate-induced VOT and AMC remains to be clarified.
Methods
The regulation and function of FHL2 in high-phosphate-induced VOT and calcification were examined in cultured VSMCs. The expression of FHL2 in AMC induced by high phosphate was examined in cultured arterial rings. The regulation of FHL2 on β-catenin and HIF-1α signaling during VOT was also examined in VSMCs, respectively.
Results
The expression of FHL2 was induced in VSMCs and arterial rings cultured in a high phosphate environment. Knockdown of FHL2 suppressed high-phosphate-induced Runx2 and osteocalcin expression and calcium deposition, whereas overexpression of FHL2 was sufficient to induce the expression of Runx2 and osteocalcin in VSMCs. Downregulation of FHL2 partially inhibited the high-phosphate-induced upregulation of active β-catenin and β-catenin-mediated gene transcription, whereas ectopic expression of FHL2 was able to induce active β-catenin and β-catenin-mediated gene transcription. Similarly, downregulation of FHL2 partially inhibited the expression of HIF-1α induced by high phosphate, while ectopic expression of FHL2 enhanced HIF-1α-mediated gene transcription, although it didn't significantly increase the expression of HIF-1α. Moreover, high phosphate induced physical interactions between FHL2 and β-catenin, FHL2 and HIF-1α, respectively, especially in the nucleus. Meanwhile, high phosphate also induced a combination of β-catenin and HIF-1α, suggesting that the high-phosphate-induced upregulation of FHL2 facilitates the formation of a FHL2/β-catenin/HIF-1α ternary complex.
Conclusion
Our results suggest that FHL2, through activating β-catenin and HIF-1α signaling, plays a notable role in regulating high-phosphate-induced VOT and could be a potential therapeutic target for AMC in patients with chronic kidney disease.
Funding
- Government Support - Non-U.S.