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

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

doi:10.1038/s42003-020-1058-2

Cited by 12 publications

(9 citation statements)

References 59 publications

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“…In addition, upon Toll-like receptor 2 (TLR2) activation, NF-kB represses expression of osteoprotegerin [ 112 ], which inherits a complex role in vascular diseases and may inhibit vascular calcification [ 113 ]. In accordance with these findings, a pro-calcific function during Pi exposure was also shown for transforming growth factor β-activated kinase 1 (TAK1), an upstream regulator of NF-kB [ 114 ]. Also, the receptor activator of NF-kB ligand (RANKL)/RANK system augments vascular calcification through NF-kB [ 115 ].…”

Section: Inflammation and Vascular Calcification In Hyperphosphatemiamentioning

confidence: 66%

Inflammation: a putative link between phosphate metabolism and cardiovascular disease

et al. 2021

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Dietary habits in the western world lead to increasing phosphate intake. Under physiological conditions, extraosseous precipitation of phosphate with calcium is prevented by a mineral buffering system composed of calcification inhibitors and tight control of serum phosphate levels. The coordinated hormonal regulation of serum phosphate involves fibroblast growth factor 23 (FGF23), αKlotho, parathyroid hormone (PTH) and calcitriol. A severe derangement of phosphate homeostasis is observed in patients with chronic kidney disease (CKD), a patient collective with extremely high risk of cardiovascular morbidity and mortality. Higher phosphate levels in serum have been associated with increased risk for cardiovascular disease (CVD) in CKD patients, but also in the general population. The causal connections between phosphate and CVD are currently incompletely understood. An assumed link between phosphate and cardiovascular risk is the development of medial vascular calcification, a process actively promoted and regulated by a complex mechanistic interplay involving activation of pro-inflammatory signalling. Emerging evidence indicates a link between disturbances in phosphate homeostasis and inflammation. The present review focuses on critical interactions of phosphate homeostasis, inflammation, vascular calcification and CVD. Especially, pro-inflammatory responses mediating hyperphosphatemia-related development of vascular calcification as well as FGF23 as a critical factor in the interplay between inflammation and cardiovascular alterations, beyond its phosphaturic effects, are addressed.

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Section: Inflammation and Vascular Calcification In Hyperphosphatemiamentioning

confidence: 66%

Inflammation: a putative link between phosphate metabolism and cardiovascular disease

et al. 2021

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“…miR-135a suppresses TGF-β-mediated epithelial-mesenchymal transition by targeting SMAD3 [31] and SMAD5 [32]. Moreover, miR-135a-5p is a key regulator of the TGFBR1/TAK1 pathway, resulting in the attenuation of vascular inflammation in rats with chronic kidney disease [33]. Our study identified that miR-135a could suppress the expression of Tgfbr1 via targeting its 3 UTR.…”

Section: For Peer Reviewmentioning

confidence: 68%

miR-135a Suppresses Granulosa Cell Growth by Targeting Tgfbr1 and Ccnd2 during Folliculogenesis in Mice

Wang

Chen

Tang

et al. 2021

Cells

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The success of female reproduction relies on high quality oocytes, which is determined by well-organized cooperation between granulosa cells (GCs) and oocytes during folliculogenesis. GC growth plays a crucial role in maintaining follicle development. Herein, miR-135a was identified as a differentially expressed microRNA in pre-ovulatory ovarian follicles between Large White and Chinese Taihu sows detected by Solexa deep sequencing. We found that miR-135a could significantly facilitate the accumulation of cells arrested at the G1/S phase boundary and increase apoptosis. Mechanically, miR-135a suppressed transforming growth factor, beta receptor I (Tgfbr1) and cyclin D2 (Ccnd2) expression by targeting their 3′UTR in GCs. Furthermore, subcellular localization analysis and a chromatin immunoprecipitation-quantitative real-time PCR (ChIP-qPCR) assay demonstrated that the TGFBR1-SMAD3 pathway could enhance Ccnd2 promoter activity and thus upregulate Ccnd2 expression. Finally, estrogen receptor 2 (ESR2) functioned as a transcription factor by directly binding to the miR-135a promoter region and decreasing the transcriptional activity of miR-135a. Taken together, our study reveals a pro-survival mechanism of ESR2/miR-135a/Tgfbr1/Ccnd2 axis for GC growth, and also provides a novel target for the improvement of female fertility.

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“…Consequently, serum DCA levels, ER stress, and ATF4 activity decrease, thereby reducing vascular calcification 39 . In CKD rat models and human aortic smooth muscle cells (HASMCs) cultured with osteogenic medium, FXR activation increases the expression of miR-135a-5p, which inhibits the transforming growth factor-β (TGFβ) receptor 1 (TGFBR1)/TGFβ-activated kinase 1 (TAK1) pathway and attenuates vascular calcification 40 .…”

Section: Role Of Fxr In Kidney Physiology and Pathophysiologymentioning

confidence: 99%

The role of the farnesoid X receptor in kidney health and disease: a potential therapeutic target in kidney diseases

et al. 2023

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The prevalence of kidney diseases has been increasing worldwide due to the aging population and has results in an increased socioeconomic burden as well as increased morbidity and mortality. A deep understanding of the mechanisms underlying the physiological regulation of the kidney and the pathogenesis of related diseases can help identify potential therapeutic targets. The farnesoid X receptor (FXR, NR1H4) is a primary nuclear bile acid receptor that transcriptionally regulates bile acid homeostasis as well as glucose and lipid metabolism in multiple tissues. The roles of FXR in tissues other than hepatic and intestinal tissues are poorly understood. In studies over the past decade, FXR has been demonstrated to have a protective effect against kidney diseases through its anti-inflammatory and antifibrotic effects; it also plays roles in glucose and lipid metabolism in the kidney. In this review, we discuss the physiological role of FXR in the kidney and its pathophysiological roles in various kidney diseases, including acute kidney injury and chronic kidney diseases, diabetic nephropathy, and kidney fibrosis. Therefore, the regulatory mechanisms involving nuclear receptors, such as FXR, in the physiology and pathophysiology of the kidney and the development of agonists and antagonists for modulating FXR expression and activation should be elucidated to identify therapeutic targets for the treatment of kidney diseases.

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

Cited by 12 publications

References 59 publications

Inflammation: a putative link between phosphate metabolism and cardiovascular disease

Inflammation: a putative link between phosphate metabolism and cardiovascular disease

miR-135a Suppresses Granulosa Cell Growth by Targeting Tgfbr1 and Ccnd2 during Folliculogenesis in Mice

The role of the farnesoid X receptor in kidney health and disease: a potential therapeutic target in kidney diseases

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