Abstract
Lipid metabolism is closely related to the improvement of vascular calcification (VC) in chronic kidney disease (CKD). Globular adiponectin (gAd) has been reported to be involved in the development of VC in CKD, but the detailed regulatory role remains unclear. The present study is aimed to investigate the biological function and the underlying regulation mechanism of gAd in the process of VC during CKD. Vascular smooth muscle cells (VSMCs) calcification was determined by Alizarin Red S staining. Protein signaling related with VC was tested by western blotting. The expression and intracellular localization of runt-related transcription factor 2 (Runx2) was detected by immunofluorescence and uraemic rat with VC was established by a two-step nephrectomy. Combined with the results of Alizarin Red S staining, we discovered that β-glycerophosphate (β-Gp)-induced the osteoblastic differentiation of VSMCs was significantly reversed by gAd treatment. Along with the VSMCs calcification and the increase of Runx2 in β-Gp-exposed VSMCs, the activities of protein kinase B (AKT) and Wnt/β-catenin pathway were enhanced, but that were counteracted by the exposure of gAd in rat and human VSMCs. After administration with agonists of the Wnt (SKL2001) and AKT (SC79), there appeared more osteoblastic differentiation and higher expression of Runx2 in gAd-treated VSMCs, but showing lower impact in the presence of SC79 than that in the presence of SKL2001. In the in vivo experiments, intravenous injection of gAd also significantly inhibited VC and Runx2 level in uraemic rat in a dose-dependent manner, possibly through regulating Wnt/β-catenin pathway. This study demonstrates that gAd ameliorates osteoblastic differentiation of VSMCs possibly by blocking PI3K/AKT and Wnt/β-catenin signaling transduction. The findings provide an important foundation for gAd in treating VC in kidney diseases.
Highlights
Cardiovascular diseases (CVD) are the leading cause of disease mortality worldwide (Franz et al 2010)
Vitamin K antagonists, direct oral anticoagulants, warfarin, heparin, parathyroid hormone and vitamin D compounds are used in chronic kidney disease (CKD) treatment (Harel et al 2014; Aursulesei and Costache 2019; Palmer et al 2007; Chen et al 2018), there are still many challenges remaining for treating vascular calcification (VC) in uremic patients
We analyzed the function of Globular adiponectin (gAd) on Vascular smooth muscle cells (VSMCs) calcification by Alizarin red S staining
Summary
Cardiovascular diseases (CVD) are the leading cause of disease mortality worldwide (Franz et al 2010). Patients with uremia often suffer from CVD (Adamczak et al 2009). Overall, compared with the general population, there is approximately 50-fold increase of CVD mortality rate in uremia dialysis patients (Hou 2005), accounting for nearly 44.2–51.0% of overall mortality (Liu et al 2014). Increased cardiovascular morbidity and mortality in uremia dialysis patients is associated with VC (Bellasi and Raggi 2012). Calcification of coronary artery and vascular tunica media contribute to the increased cardiovascular mortality. Artery calcification in uremic patients induces cardiovascular stiffening, leading to systolic hypertension, left ventricular hypertrophy and reduced coronary perfusion (London 2013).
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