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

Commun Biol. 2020 Jun 24;3(1):327. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / cytology
  • Calcinosis / genetics
  • Calcinosis / metabolism*
  • Cells, Cultured
  • Female
  • Humans
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism
  • Male
  • MicroRNAs / genetics*
  • Muscle, Smooth, Vascular / cytology
  • Osteogenesis
  • Rats, Wistar
  • Receptor, Transforming Growth Factor-beta Type I / genetics
  • Receptor, Transforming Growth Factor-beta Type I / metabolism
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Renal Insufficiency, Chronic / etiology
  • Renal Insufficiency, Chronic / pathology
  • Vasculitis / genetics
  • Vasculitis / metabolism*
  • Vasculitis / pathology

Substances

  • MIRN135 microRNA, human
  • MicroRNAs
  • Receptors, Cytoplasmic and Nuclear
  • farnesoid X-activated receptor
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human