Secreted Frizzled-Related Protein 5 Attenuates High Phosphate-Induced Calcification in Vascular Smooth Muscle Cells by Inhibiting the Wnt/ß-Catenin Pathway

Deng, Dai; Diao, Zongli; Han, Xue; Liu, Wenhu

doi:10.1007/s00223-016-0117-7

Cited by 38 publications

(32 citation statements)

References 28 publications

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“…Our study indicated that Wnt pathway was involved in CKD VC, which is consistent with previous studies . Addition of Wnt pathway inhibitor secreted frizzeled‐related protein 5 could inhibit high phosphate‐induced calcification of VSMCs .…”

Section: Disccusionsupporting

confidence: 92%

“…These two factors are both involved in canonical Wnt pathway. Several other canonical Wnt pathway factors including Wnt8b and Frizzled‐related protein have also been suggested to play roles in phosphate‐induced calcification in VSMC . However, Wnt5a, a non‐canonical Wnt pathway factor, was not significantly associated with VC in our study.…”

Section: Disccusioncontrasting

confidence: 80%

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Vascular calcification is associated with Wnt‐signaling pathway and blood pressure variability in chronic kidney disease rats

Liao

Wang

et al. 2019

Nephrology

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Aim Vascular calcification (VC) is a common complication in chronic kidney disease (CKD) and has been shown to be associated with increased cardiovascular events and mortality. This study was to explore the role of Wnt‐signaling pathway in CKD VC, and the association between VC and blood pressure variability (BPV) which is a risk factor of cardiovascular events. Methods Adult male Sprague‐Dawley rats were divided into adenine‐induced CKD group (n = 5), 5/6 nephrectomy CKD group (n = 5), sham group (n = 5) and control group (n = 5). Low‐calcium‐high‐phosphate diets were introduced to induce vascular calcification. Both daytime (hour‐to‐hour during the day) and mid‐term (day‐to‐day for 9 days) blood pressure (BP) were collected and analyzed for BPV metrics. At sacrifice, kidney, heart and aorta samples were taken for histological analyses. Calcium deposition in aorta was identified with Alizarin Red stain and graded. Immunohistochemistry stain and western blot were performed for Wnt3a, Wnt5a, β‐catenin, sclerostin, osteopontin, and α‐SMA. Results Compared with control rats, CKD rats suffered from markedly severer VC (Grade 2.6 ± 0.2 and 1.8 ± 0.8 vs 0.0 ± 0.0 and 0.2 ± 0.4, P = .0010). VC was positively correlated with vascular Wnt3a and β‐catenin expression (P = .0032 and .0000), but not significantly associated with Wnta5a or sclerostin. Besides, CKD rats showed increased BPV (P < .001), which was also positively correlated with VC. Conclusion We confirmed that CKD rats had enhanced Wnt‐signaling in vascular tissue and severer aorta calcification together with increased BPV. Wnt pathway may be a potential target in future VC and BPV management in CKD.

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Section: Disccusionsupporting

confidence: 92%

Section: Disccusioncontrasting

confidence: 80%

Vascular calcification is associated with Wnt‐signaling pathway and blood pressure variability in chronic kidney disease rats

Liao

Wang

et al. 2019

Nephrology

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“…The link between SFRP5 and renal function has not been investigated in detail yet. One study reported that SFRP5 inhibited high phosphate-induced calcification of vascular smooth muscle cells which is a major cardiovascular risk factor in chronic kidney disease (CKD) [30]. However, another study showed that the Sfrp5 gene is hypermethylated and downregulated in a mouse model of CKD, whereas injection of recombinant Sfrp5 inhibited Wnt signaling and attenuated renal fibrosis [31].…”

Section: Discussionmentioning

confidence: 99%

Inverse associations between serum levels of secreted frizzled-related protein-5 (SFRP5) and multiple cardiometabolic risk factors: KORA F4 study

Carstensen‐Kirberg

Kannenberg

Huth

et al. 2017

Cardiovasc Diabetol

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AimsSecreted frizzled-related protein (Sfrp)5 has beneficial effects on insulin sensitivity, inflammation and cardiovascular risk in different mouse models, but its relevance for cardiometabolic diseases in humans is controversial. We aimed to characterise associations of circulating SFRP5 with cardiometabolic risk factors and prediabetes/type 2 diabetes in a large population-based cohort.MethodsCross-sectional associations between serum SFRP5 and cardiometabolic risk factors as well as prediabetes/type 2 diabetes were investigated in 1096 participants aged 62–81 years from the German KORA F4 study, of whom 666 had prediabetes or type 2 diabetes. Multivariable linear regression models were adjusted for potential confounders including age, sex, body mass index (BMI), lifestyle factors, lipids, hypertension, kidney function and myocardial infarction.ResultsHigher serum SFRP5 levels were associated with lower HbA1c, BMI, systolic blood pressure, estimated glomerular filtration rate and high-sensitivity C-reactive protein levels and with higher levels of high-density lipoprotein cholesterol and adiponectin in the fully adjusted model (all P < 0.009). In contrast, favourable associations between SFRP5 and glycaemia, insulin, insulin resistance and other cardiometabolic risk factors were attenuated after adjustment for BMI. Serum SFRP5 levels were lower in participants with prediabetes or type 2 diabetes [(median (25th; 75th percentile) 48.8 (35.5; 65.7) ng/ml] compared to participants with normal glucose tolerance [55.9 (42.6; 69.6) ng/ml] (P < 0.001). In the fully adjusted model, higher SFRP5 was associated with lower odds of prediabetes/type 2 diabetes [OR (95% CI) (0.72 (0.58; 0.89)) per doubling of SFRP5, P < 0.01].ConclusionsHigher serum SFRP5 was inversely associated with multiple risk factors for type 2 diabetes and cardiovascular diseases. However, BMI represents a strong confounder of some of these associations. Higher circulating SFRP5 was also associated with lower odds of prediabetes/type 2 diabetes, and this association was independent of BMI. Thus, SFRP5 emerges as novel biomarker that merits further research in the context of prevention of cardiometabolic diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-017-0591-x) contains supplementary material, which is available to authorized users.

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“…In addition, BMP‐9 was also been reported to induce VC through activating the Wnt/β‐catenin pathway . In contrast, Deng et al revealed secreted frizzled‐related protein 5 (SFRP5) attenuates high phosphate‐induced calcification in vascular smooth muscle cells by inhibiting the Wnt/β‐catenin pathway . Thus, Wnt/β‐catenin pathway was generally identified as an inducer of vascular calcification, and regulated by several signal molecules, including BMP family and SFRP5.…”

Section: Discussionmentioning

confidence: 99%

Klotho/FGF23 axis mediates high phosphate‐induced vascular calcification in vascular smooth muscle cells via Wnt7b/β‐catenin pathway

Chen

Huang

Duan

et al. 2019

The Kaohsiung J of Med Scie

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Vascular calcification (VC) plays as a critical role on cardiovascular disease (CVD) and acts as a notable risk factor in cardiovascular system. Vascular smooth muscle cells (VSMCs) calcification can be triggered by high phosphate treatment; however, the explicit mechanism remains unclear. In the present study, we isolated VSMCs from primary rat artery, applied β‐GP (β‐glycerophosphate) for inducing VSMCs calcification in vitro to explore the mechanism of phosphate‐induced calcification in VSMCs. Alizarin red staining was performed to assess the mineralization in VSMCs. Calcium deposition experiment was taken to evaluate the calcium content. ALP staining was determined to assess the ALP activity. The recombinant adenoviruses were constructed for the overexpression of Klotho and FGF23, respectively. qRT‐PCR and western blot analysis were subjected to measure the expression of Klotho/FGF23 and correlated genes among Wnt7b/β‐catenin pathway. We found that the calcium content was obviously increased and Alizarin red staining was positive in calcification group exposure with high phosphate in a time‐dependent manner. The expression of Klotho and FGF23 was significantly decreased in the calcification group. However, overexpression of Klotho and FGF23 markedly reversed VSMCs calcification stimulating with high phosphate treatment. Moreover, Wnt7b/β‐catenin inhibitor DKK1 could partly attenuate the effect of high phosphate on calcified VSMCs. These findings demonstrated that Klotho/FGF23 axis could modulate high phosphate‐induced VSMCs calcification via Wnt7b/β‐catenin signaling pathway. Our findings unravel that Klotho/FGF23‐ Wnt7b/β‐catenin axis functions as a crucial role in the VSMCs calcification.

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Secreted Frizzled-Related Protein 5 Attenuates High Phosphate-Induced Calcification in Vascular Smooth Muscle Cells by Inhibiting the Wnt/ß-Catenin Pathway

Cited by 38 publications

References 28 publications

Vascular calcification is associated with Wnt‐signaling pathway and blood pressure variability in chronic kidney disease rats

Vascular calcification is associated with Wnt‐signaling pathway and blood pressure variability in chronic kidney disease rats

Inverse associations between serum levels of secreted frizzled-related protein-5 (SFRP5) and multiple cardiometabolic risk factors: KORA F4 study

Klotho/FGF23 axis mediates high phosphate‐induced vascular calcification in vascular smooth muscle cells via Wnt7b/β‐catenin pathway

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