Farnesoid X receptor activation inhibits TGFBR1/TAK1-mediated vascular inflammation and calcification via miR-135a-5p

Chao Li,Zhibo Gai,Wenqing Yang,Ting Gui,Yunlun Li,Jingkang Ji,Shijun Zhang,Xiaoqing Chen

doi:10.1038/s42003-020-1058-2

Abstract

Chronic inflammation plays a crucial role in vascular calcification. However, only a few studies have revealed the mechanisms underlying the development of inflammation under high-phosphate conditions in chronic kidney disease (CKD) patients. Here, we show that inflammation resulting from the activation of the TGFBR1/TAK1 pathway is involved in calcification in CKD rats or osteogenic medium-cultured human aortic smooth muscle cells (HASMCs). Moreover, miR-135a-5p is demonstrated to be a key regulator of the TGFBR1/TAK1 pathway, which has been reported to be decreased in CKD rats. We further reveal that farnesoid X receptor (FXR) activation increases miR-135a-5p expression, thereby inhibiting the activation of the TGFBR1/TAK1 pathway, ultimately resulting in the attenuation of vascular inflammation and calcification in CKD rats. Our findings provide advanced insights into the mechanisms underlying the development of inflammation in vascular calcification, and evidence that FXR activation could serve as a therapeutic strategy for retarding vascular calcification in CKD patients.

Highlights

Chronic inflammation plays a crucial role in vascular calcification
Several studies have indicated that the Transforming growth factor-β (TGF-β)/ Smad[3] and BMP2 pathways are directly involved in vascular calcification[33,34]; to date, no evidence has demonstrated whether the TGFBR1/TGF-β-activated kinase 1 (TAK1) pathway is a key potential target of osteogenic medium-induced human aortic smooth muscle cells (HASMCs) inflammation, which may be responsible for vascular calcification
The further experiments indicated that TGFBR1 is a crucial target of HASMC inflammation, which was indicated by the decrease in the expression of nuclear factor-κB (NF-κB) and TNF-α after TGFBR1 silencing in HASMCs cultured in osteogenic medium (Figs. 1f and 1e)

Summary

Introduction

Chronic inflammation plays a crucial role in vascular calcification. only a few studies have revealed the mechanisms underlying the development of inflammation under high-phosphate conditions in chronic kidney disease (CKD) patients. We show that inflammation resulting from the activation of the TGFBR1/TAK1 pathway is involved in calcification in CKD rats or osteogenic medium-cultured human aortic smooth muscle cells (HASMCs). We further reveal that farnesoid X receptor (FXR) activation increases miR-135a-5p expression, thereby inhibiting the activation of the TGFBR1/TAK1 pathway, resulting in the attenuation of vascular inflammation and calcification in CKD rats. Vascular calcification is associated with an increased risk of cardiovascular mortality in patients with chronic kidney disease (CKD), independent of classical cardiovascular risk factors[1,2,3]. It is a prominent feature of atherosclerosis that occurs either at the intima or the tunica media. Whether the TGF-β pathway plays the role of a protagonist in attenuating the formation of vascular calcification by regulating inflammatory responses is yet to be ascertained

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