Abstract
Objective: Vascular calcification (VC) is an important predictor of cardiovascular morbidity and mortality in patients with chronic renal failure (CRF). It is well-known that obesity and metabolic syndrome (OB/MS) predicts poor prognosis of CRF patients. However, the influence of OB/MS on VC in CRF patients isn't clear. IL-18 mediates OB/MS-related inflammation, but whether IL-18 is involved in OB/MS -mediated VC in CRF patients hasn't been studied. In this study, it was explored that whether OB/MS caused by high-fat diet (HFD) can affect the level of serum IL-18 and aggravate the degree of VC in CRF rats. Furthermore, it was studied that whether IL-18 induces rat vascular smooth muscle cells (VSMCs) calcification by activating the MAPK pathways.Approach: The rats were randomly assigned to the sham-operated, CRF and CRF + HFD groups. CRF was induced by 5/6 nephrectomy. Serum IL-18 levels and aortic calcification indicators were compared in each group. Primary rat VSMCs calcification were induced by β-glycerophosphate and exposed to IL-18. VSMCs were also treated with MAPK inhibitors.Results: The weight, serum levels of hsCRP, TG and LDL-C in CRF + HFD group were significantly higher than those in sham-operated and CRF groups (p < 0.05). Compared with the sham-operated group, the calcium content and the expression of BMP-2 of aorta in CRF and CRF + HFD groups were significantly increased (p < 0.05). Moreover, the calcium content and the expression of BMP-2 of aorta in CRF + HFD group was significantly higher than those in CRF group (p < 0.05). And the serum IL-18 level was positively correlated with aortic calcium content. It was also found that p38 inhibitor SB203580 can suppress the VSMCs calcification and osteoblast phenotype differentiation induced by IL-18. But the JNK inhibitor SP600125 can't suppress the VSMCs calcification and osteoblast phenotype differentiation induced by IL-18.Conclusions: These findings suggest that obesity-related inflammation induced by high-fat diet could exacerbate VC in CRF rats. Furthermore, serum IL-18 level had a positive correlation with the degree of VC. It is also found that IL-18 promoted osteogenic differentiation and calcification of rat VSMCs via p38 pathway activation.
Highlights
Specialty section: This article was submitted to General Cardiovascular Medicine, a section of the journal Frontiers in Cardiovascular Medicine
It was found that p38 inhibitor SB203580 can suppress the vascular smooth muscle cells (VSMCs) calcification and osteoblast phenotype differentiation induced by IL-18
Serum IL-18 level had a positive correlation with the degree of Vascular calcification (VC)
Summary
Animal Model and GroupingThe animal experiments were approved by the Committee on Ethics of Animal Experiments and conducted in accordance with the Guidelines for Animal Experiments, Sun Yat-sen University and the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No 85-23, revised 1996).Male Sprague-Dawley rats with an average body weight of 200–250 g were used in this study. The rats were randomly assigned to the CRF and sham-operated groups. CRF was induced by 5/6 nephrectomy (5/6 Nx) with surgical excision of two-thirds of the left kidney, followed by the complete right nephrectomy 1 week later. Sham-operated group underwent similar surgical procedures but with only removal of the renal envelope. The 5/6 Nx rats were randomly divided into CRF and CRF + high fat diet (HFD) groups. The sham-operated and CRF groups were fed a standard laboratory diet with a total fat content of 4.3%. The CRF + HFD group were fed a HFD with a total fat content of 34.9%. Rats were sacrificed and serum levels of IL-18 were measured with commercially available kits (Ab Frontier). The aortas were dissected for calcium deposition assay, von Kossa and Alizarin red S staining, RNA and protein extraction
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