Kaempferol is an estrogen‐related receptor α and γ inverse agonist

Wang, Junjian; Fang, Fang; Huang, Zhiyan; Wang, Yanfei; Wong, Chi‐Wai

doi:10.1016/j.febslet.2009.01.030

Cited by 75 publications

(70 citation statements)

References 25 publications

(28 reference statements)

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“…In the present study, high glucose treatment was demonstrated to increase the expression of EERα at the mRNA and protein levels. Collectively, these data may indicate a potential role for EERα in DR. Kaempferol has been shown to be an ERRα inverse agonist that is able to inhibit cell growth by antagonizing ERRα (14), and its anticancer effect has also been recognized (12,13). However, its role in DR has not previously been reported.…”

Section: Discussionmentioning

confidence: 99%

“…Kaempferol (3,4',5,7-tetrahydoxyflavone), a commonly found dietary flavonoid, has been isolated from grapefruit, tea, broccoli and other plant sources (11). The anticancer effects of kaempferol have been demonstrated in previous studies (12,13), and kaempferol has been found to act as an ERRα inverse agonist, which inhibits cell growth in different cancer cell lines by antagonizing ERRα activity (14). Kaempferol has been shown to have an anti-angiogenic effect in ovarian cancer (15); however, whether kaempferol inhibits angiogenesis in DR is unclear.…”

Section: Introductionmentioning

confidence: 99%

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Kaempferol targets estrogen‑related receptor α and suppresses the angiogenesis of human retinal endothelial cells under high glucose conditions

Zhang

2017

Exp Ther Med

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Abstract. Diabetic retinopathy (DR) is the most common complication of diabetes and a major cause of new-onset blindness in the developed world. The present study aimed to examine the effect of kaempferol on high glucose-induced human retinal endothelial cells (HRECs) in vitro. The expression levels of various mRNAs and proteins were measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting, respectively. The target of kaempferol was determined using a luciferase reporter assay. In addition, HREC proliferation, migration and cell sprouting were determined using Cell Counting kit-8, wound scratch and tube formation assays, respectively. RT-qPCR and western blotting results showed that treatment with 30 mM glucose for 12, 24 and 48 h increased the expression level of estrogen-related receptor α (ERRα) mRNA and protein.The luciferase reporter assay demonstrated that kaempferol inhibited ERRα activity in HRECs. Compared with 5 mM normal glucose treatment, high (30 mM) glucose significantly promoted the proliferation, migration and tube formation of HRECs, which was antagonized by 10 and 30 µM kaempferol in a dose-dependent manner. Treatment with 30 mM glucose also increased the expression of vascular endothelial growth factor (VEGF) mRNA and protein, and the expression levels of VEGF mRNA and protein were suppressed by kaempferol (10 and 30 µM). Kaempferol (30 µM) treatment also increased the expression levels of thrombospondin 1 (TSP-1) and a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS-1) mRNA; however, TSP-1 and ADAMTS-1 levels did not differ between high glucose and normal (5 mM) glucose conditions. The results of this study suggest that kaempferol targets ERRα and suppresses the angiogenesis of HRECs under high glucose conditions. Kaempferol may be a potential drug for use in controlling the progression of DR; however, in vivo studies are required to evaluate its efficacy and safety.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Kaempferol targets estrogen‑related receptor α and suppresses the angiogenesis of human retinal endothelial cells under high glucose conditions

Zhang

2017

Exp Ther Med

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“…ERR␥ Inverse Agonist GSK5182 Enhances Overexpressed SMILE to Down-regulate the Expression of ERR␥ Target Gene-Next, we performed ChIP assays to examine whether SMILE associates with the ERR␥ on the promoter of PDK4, a known target of ERR␥ (42,43). Specific primers that flanked an ERRE AGGTCA in the PDK4 promoter were used for quantitative real time PCR analysis (Fig.…”

Section: Smile Is Required For the Err␥ Inverse Agonist Gsk5182-mediatedmentioning

confidence: 99%

Transcriptional Corepressor SMILE Recruits SIRT1 to Inhibit Nuclear Receptor Estrogen Receptor-related Receptor γ Transactivation

Xie

Park

Kim

et al. 2009

Journal of Biological Chemistry

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SMILE (small heterodimer partner interacting leucine zipper protein) has been identified as a corepressor of the glucocorticoid receptor, constitutive androstane receptor, and hepatocyte nuclear factor 4␣. Here we show that SMILE also represses estrogen receptor-related receptor ␥ (ERR␥) transactivation. Knockdown of SMILE gene expression increases ERR␥ activity. SMILE directly interacts with ERR␥ in vitro and in vivo. Domain mapping analysis showed that SMILE binds to the AF2 domain of ERR␥. SMILE represses ERR␥ transactivation partially through competition with coactivators PGC-1␣, PGC-1␤, and GRIP1. Interestingly, the repression of SMILE on ERR␥ is released by SIRT1 inhibitors, a catalytically inactive SIRT1 mutant, and SIRT1 small interfering RNA but not by histone protein deacetylase inhibitor. In vivo glutathione S-transferase pulldown and coimmunoprecipitation assays validated that SMILE physically interacts with SIRT1. Furthermore, the ERR␥ inverse agonist GSK5182 enhances the interaction of SMILE with ERR␥ and SMILE-mediated repression. Knockdown of SMILE or SIRT1 blocks the repressive effect of GSK5182. Moreover, chromatin immunoprecipitation assays revealed that GSK5182 augments the association of SMILE and SIRT1 on the promoter of the ERR␥ target PDK4. GSK5182 and adenoviral overexpression of SMILE cooperate to repress ERR␥-induced PDK4 gene expression, and this repression is released by overexpression of a catalytically defective SIRT1 mutant. Finally, we demonstrated that ERR␥ regulates SMILE gene expression, which in turn inhibits ERR␥. Overall, these findings implicate SMILE as a novel corepressor of ERR␥ and recruitment of SIRT1 as a novel repressive mechanism for SMILE and ERR␥ inverse agonist.

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“…ERRgamma constitutive activity can be enhanced or stabilized by the synthetic agonist GSK4716 (Yu and Forman, 2005;Zuercher et al, 2005), the endocrine disruptor Bisphenol A (BPA) (Matsushima et al, 2007;Takayanagi et al, 2006), and a variant of this compound (4-alpha-cumylphenol) (Matsushima et al, 2008). ERRgamma constitutive activity has also recently been shown to be inhibited by kaempferol, a dietary flavonoid (Wang et al, 2009). Coactivators/Corepressors: Like other nuclear receptors, ERRgamma transcriptional activity is modulated by binding to other proteins that can serve as coactivators or corepressors.…”

Section: Dbdmentioning

confidence: 99%