Leptin promotes endothelial dysfunction in chronic kidney disease through AKT/GSK3β and β-catenin signals

https://doi.org/10.1016/j.bbrc.2016.10.079Get rights and content

Highlights

  • Serum leptin was elevated in CKD patients and it was associated with endothelial dysfunction.

  • Leptin induced endothelial dysfunction by remodeling cytoskeleton in HUVECs.

  • Leptin promoted endothelial dysfunction via a mechanism involving the AKT/GSK3β and β-catenin signals.

Abstract

Endothelial dysfunction (ED) is a well-recognized instigator of cardiovascular diseases and develops in chronic kidney disease (CKD) with high rate. Recent studies have implicated that leptin is associated with endothelial dysfunction. We investigated the relationship between leptin and markers of ED in CKD patients and how leptin contributed to endothelial damage. 140 CKD patients and 140 healthy subjects were studied. Serum leptin levels were significantly higher in CKD than in controls and displayed significantly positive association with the increase levels of sICAM-1 and sVCAM-1 but negative correlation with flow-mediated dilatation (FMD) reduction in patients. Our in vitro study demonstrated that leptin induced overexpression of ICAM-1 and VCAM-1, led to f-actin reorganization and vinculin assembly, increased endothelial monolayer permeability for FITC-dextran, and accelerated endothelial cell migration; these changes were markedly reversed when the cells were transfected with AKT or β-catenin shRNA vectors. Notably, high leptin resulted in hyper-phosphorylation of AKT and GSK3β, along with nuclear accumulation of β-catenin. In conclusion, serum leptin was elevated in CKD patients and it might contribute to endothelial dysfunction by disarrangement of f-actin cytoskeleton via a mechanism involving the AKT/GSK3β and β-catenin pathway.

Introduction

In the past decades, chronic kidney disease (CKD) has attracted global attention due to its high prevalence, deleterious effects, and tremendous health care expenditures. CKD, even at an early stage, is strongly associated with increased risk of mortality and cardiovascular disease (CVD) [1]. However, the high prevalence and incidence of cardiovascular disease in chronic kidney disease cannot be adequately explained by traditional risk factors. Therefore, other non-traditional risk factors such as endothelial dysfunction have aroused both nephrologist and cardiologist's great interest.

Leptin is a pleiotropic hormone mainly produced in adipose tissue. Except regulating food intake and energy expenditure, leptin has been shown to be involved in many other important physiological processes. It's well accepted that leptin functions as pro-inflammatory molecule and inflammation is a common promoter associated with cardiovascular events. Recent animal studies have reported that leptin administration can induce high blood pressure and proteinuria [2]. Several clinical studies have revealed positive correlations between leptin and cardiovascular parameters, such as myocardial infarction, arterial rigidity and coronary atherosclerosis [3]. All these facts suggest a role of leptin as a mediator of cardiovascular diseases. Leptin is cleared from the circulation by the kidney through glomerular filtration and metabolic degradation in renal tubules and many studies have reported elevation of serum leptin levels in CKD patients [4]. However, previous researches offered suggestive but limited evidence for a pathogenic role of leptin in CKD. Especially, data about the influence of leptin on the endothelium status in adults with CKD are scarce.

Hence, the present study was done to evaluate the serum concentration changes of leptin in CKD patients compared with healthy subjects, analyze the putative association between leptin and endothelial function in CKD adults and then explore how leptin contributes to endothelial dysfunction via in vitro experiments. In view that both AKT [5] and β-catenin [6] have been implicated in a diverse assay of endothelial events, such as cell migration, cell adhesion and actin cytoskeleton reorganization, we also knocked down AKT or β-catenin gene to detect the effects of AKT or β-catenin signaling pathway on cultured HUVECs in response to leptin stimulation and to investigate the interaction of AKT and β-catenin under high leptin condition, which aimed at finding out a potential protective mechanism for endothelium.

Section snippets

Study population

A total of 140 non-diabetic, clinical stable CKD patients and 140 healthy subjects who were age- and gender-matched were enrolled in this study. Patients were diagnosed as CKD according to National Kidney Foundation K/DOQI Guideline [7]. Exclusion criteria of patients were: history of chronic dialysis, kidney transplants, immunotherapy in the past six months, chemotherapy within the past two years, or current intervention clinical trial participation; systemic inflammatory illness or history of

Anthropometric and metabolic characteristics

The anthropometric and clinical characteristics of the study population were reported in Table 2. There was no significant difference in gender, age and BMI between patients and normal controls. When compared with healthy subjects, CKD patients displayed significantly higher serum total cholesterol, triglyceride and lower HDL-c, as well as fasting glucose and HOMA-IR. Moreover, CKD patients were prone to develop inflammation status, which represented by higher hs-CRP levels than controls.

Serum adhesion molecule levels are increased and FMD is decreased in CKD patients than controls

As

Discussion

When it's come to CKD, CVD is always an inevitable question because of its high prevalence and incidence in CKD patients. There are a large of risk factors contributing to CVD in CKD, however, whatever risk mediator comes, endothelium, as the organ lining the innermost surface of the entire circulatory system, always stands in the breach as a common pathway. Thus, assessing endothelial dysfunction is important in understanding the onset of CVD, developing new potential interventions ahead of

Conflicts of interest

All authors declare no conflict of interest.

Acknowledgments

This work was supported by National Natural Science Foundation of China (Grant 30971381, 81370834 and 81400732), Shandong Young Scientists Award Fund (2010BSB14076) and Chinese Society of Nephrology Scientific Fund (14050480585).

References (21)

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