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

Abstract

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.

Inflammation and Premature Ageing in Chronic Kidney Disease

“…Conversely, shRNA-mediated knockdown of beta-catenin in CKD rats on a high-phosphate diet reduced vascular calcification [79]. Interestingly, klotho is an inhibitor of the Wnt/beta-catenin pathway [70], ameliorating high P i -induced VSMC calcification [81], as well as inhibiting osteogenic transition of these cells [82,83]. Taken together, P i induces EVA at least in part by the Wnt/beta-catenin pathway, and different treatment approaches potentially mitigate the adverse effects of P i on EVA, including klotho.…”

“…Kidney-derived klotho is of particular interest as a potential treatment for inflammation and premature ageing in CKD, because klotho-deficient mice and patients with CKD have similar phenotypes, such as EVA and a pro-inflammatory status, and klotho is related to ageing in both humans and mice [70,72]. Similar to the NRF2 system, klotho is repressed in CKD, and stimulation of klotho can ameliorate oxidative stress and mitochondrial function [108], renal fibrosis [152], inflammation [72], as well as premature ageing [108], including EVA [55,[81][82][83][111][112][113].…”

Analysis of Wnt7B and BMP4 expression patterns in congenital pulmonary airway malformation

“…The signaling molecule Wnt7B is a positive regulator of the Wnt/β‐catenin pathway 17 . The gene for Wnt7B is located on human chromosome 22q13.3 18 .…”

“…The signaling molecule Wnt7B is a positive regulator of the Wnt/ β-catenin pathway. 17 The gene for Wnt7B is located on human chromosome 22q13.3. 18 The Wnt7B protein is the only member of autocrine/paracrine signaling molecule group whose expression is restricted to the airway epithelium during embryonic lung development and with markedly upregulated transcription during the pseudoglandular period.…”

Fibroblast Growth Factor 21 Predicts and Promotes Vascular Calcification in Haemodialysis Patients

“…Clinical studies indicate a correlation between higher FGF23 levels and increased aortic calci cation. [13,14] However, other studies have shown that FGF23 had no impact on VC [15,16] or inhibited the progression of VC [17,18]. FGF21 is also increased progressively with a decline of renal function.…”