FHL2 in arterial medial calcification in chronic kidney disease

Yuan-Ru Liao; Yu-Cheng Tsai; Tsung-Han Hsieh; Ming-Tsun Tsai; Feng-Yen Lin; Shing-Jong Lin; Chih-Ching Lin; Hou-Yu Chiang; Pao-Hsien Chu; Szu-Yuan Li

doi:10.1093/ndt/gfae091

FHL2 in arterial medial calcification in chronic kidney disease

Nephrol Dial Transplant. 2024 Apr 25:gfae091. doi: 10.1093/ndt/gfae091. Online ahead of print.

Authors

Yuan-Ru Liao^{1

2}, Yu-Cheng Tsai^{1

2}, Tsung-Han Hsieh³, Ming-Tsun Tsai^{1

4}, Feng-Yen Lin⁵, Shing-Jong Lin⁵, Chih-Ching Lin^{1

4}, Hou-Yu Chiang^{6

7

8}, Pao-Hsien Chu⁶, Szu-Yuan Li^{1

4}

Affiliations

¹ Division of Nephrology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
² Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.
³ Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, Taiwan.
⁴ School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
⁵ Division of Cardiology, Department of Internal Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan.
⁶ Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
⁷ Department of Anatomy, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
⁸ Graduate Institute of Biomedical Science, College of Medicine, Chang Guang University, Taoyuan, Taiwan.

PMID: 38664060
DOI: 10.1093/ndt/gfae091

Abstract

Background and hypothesis: Arterial medial calcification (AMC) is a common complication in individuals with chronic kidney disease (CKD), which can lead to cardiovascular morbidity and mortality. The progression of AMC is controlled by a key transcription factor called runt-related transcription factor 2 (RUNX2), which induces vascular smooth muscle cells (VSMCs) transdifferentiation into a osteogenic phenotype. However, RUNX2 has not been targeted for therapy due to its essential role in bone development. The objective of our study was to discover a RUNX2 coactivator that is highly expressed in arterial VSMCs as a potential therapy for AMC.

Methods: We employed transcriptomic analysis of human data and an animal reporter system to pinpoint FHL2 as a potential target. Subsequently, we investigated the mRNA and protein expression patterns of FHL2 in the aortas of both human and animal subjects with CKD. To examine the role of FHL2 in the RUNX2 transcription machinery, we conducted coimmunoprecipitation (Co-IP) and chromatin immunoprecipitation (ChIP) experiments. Next, we manipulated FHL2 expression in cultured VSMCs to examine its impact on high phosphate-induced transdifferentiation. Finally, we employed FHL2 null mice to confirm the role of FHL2 in the development of AMC in vivo.

Results: Among all the potential RUNX2 cofactor, FHL2 displays selective expression within the cardiovascular system. In the context of CKD subjects, FHL2 undergoes upregulation and translocation from the cytosol to the nucleus of arterial VSMCs. Once in the nucleus, FHL2 interacts structurally and functionally with RUNX2, acting as a coactivator of RUNX2. Notably, the inhibition of FHL2 expression averts transdifferentiation of VSMCs into an osteogenic phenotype and mitigates aortic calcification in uremic animals, without causing any detrimental effects on the skeletal system.

Conclusion: These observations provide evidence that FHL2 is a promising target for treating arterial calcification in patients with CKD.

Keywords: FHL2; RUNX2; kidney disease; vascular calcification; vascular smooth muscle cell.