The m6A Eraser FTO Drives CKD-Associated Vascular Calcification Through Posttranscriptional Activation of ANKRD1 - International Society of Nephrology Events

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Abstract Title *

The m6A Eraser FTO Drives CKD-Associated Vascular Calcification Through Posttranscriptional Activation of ANKRD1

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Presenter First Name

Tingru

Presenter Surname

Lin

Co-author 1

Tingru Lin tingru_lin1997@163.com Peking University People's Hospital Nephrology Beijing China *

Co-author 2

Xinyu Zhang 2411110383@stu.pku.edu.cn Peking University People's Hospital Nephrology Bejing China -

Co-author 3

Li Zhu zhuli3714@126.com Peking University People's Hospital Nephrology Bejing China -

Co-author 4

LiangYing Gan ganl@bjmu.edu.cn Peking University People's Hospital Nephrology Bejing China -

Co-author 5

Li Zuo zuoli@bjmu.edu.cn Peking University People's Hospital Nephrology Bejing China -

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Introduction

N6-methyladenosine (m6A) is the most important internal chemical modification of mRNA and plays a key role in various cardiovascular diseases. The demethylase FTO serves a significant function, particularly in osteogenesis and cardiac valve calcification. However, the role of FTO in the pathogenesis of chronic kidney disease (CKD)-related vascular calcification remains unclear.

Methods

In this study, we revealed significantly decreased m6A methylation in calcified vasculature from Chronic kidney disease and showed that the abnormal m6A level resulted mainly from upregulation of the demethylase fat mass and obesity-associated protein (FTO). Gain- and loss-of-function studies established FTO as a key driver of vascular calcification in CKD. Combined m6A and RNA sequencing (RNA-seq) and subsequent validation and functional studies identified Ankyrin Repeat Domain Protein 1 (ANKRD1) as a functional target of FTO-mediated m6A modification.FTO significantly promotes vascular smooth muscle cells osteogenic transdifferentiation by targeting ANKRD1. The effect of an FTO inhibitor on vascular calcification was evaluated in a rat model of CKD-related vascular calcification induced by 5/6 nephrectomy plus a high-phosphate diet and calcitriol injections.

Results

m6A methylation levels were significantly decreased in vascular tissues from patients with calcification, primarily resulting from the upregulation of the demethylase FTO.FTO played a pro-calcific role, promoting the vascular calcification phenotype.Ankyrin Repeat Domain Protein 1 (ANKRD1) was identified as a key downstream target of FTO-mediated m6A modification. FTO reduced the m6A modification level of ANKRD1 mRNA, thereby promoting the osteogenic differentiation of vascular smooth muscle cells (VSMCs) and the expression of osteogenesis-related genes.In the animal model, using an FTO inhibitor effectively attenuated the degree of vascular calcification. In vitro, knocking down or inhibiting FTO suppressed the osteogenic phenotype of cells, while overexpressing FTO promoted the osteogenic phenotype in VSMCs. Similarly, knocking down or overexpressing ANKRD1 inhibited or promoted VSMC osteogenic differentiation, respectively.

Conclusion

This study elucidates the critical role of the m6A demethylase FTO in driving CKD-related vascular calcification and proposes a novel **FTO-ANKRD1 signaling axis as a potential effective therapeutic target for this disease.

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