Biochemical and Biophysical Research Communications
Leptin promotes endothelial dysfunction in chronic kidney disease through AKT/GSK3β and β-catenin signals
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).
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