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NDT Advance Access published online on December 8, 2007
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfm631
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@ oxfordjournals.org


Increased Serum Advanced Glycation End Products is Associated with Impairment in Hdl Antioxidative Capacity in Diabetic Nephropathy

Huali Zhou, Kathryn CB Tan, Sammy WM Shiu and Ying Wong

Department of Medicine, University of Hong Kong, Pokfulam Road, Hong Kong

Correspondence and offprint requests to: Dr. Kathryn Tan, Department of Medicine, University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong. Tel: +852-2855-4769; Fax: +852-2816-2187; E-mail: kcbtan{at}hkucc.hku.hk



   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Background. Advanced glycation end products (AGEs) play an important role in the pathogenesis of diabetic complications. Recent data suggest that AGEs may also interfere with the function of HDL and the reverse cholesterol transport pathway. We have investigated whether serum AGE level is associated with impairment in the antioxidative capacity of HDL and in the ability of serum to induce cholesterol efflux in type 2 diabetic patients with and without nephropathy.

Methods. A total of 167 controls and 264 diabetic patients was recruited. The ability of serum to induce cellular cholesterol efflux and the capacity of HDL to inhibit LDL oxidation ex vivo was determined. Serum AGEs were assayed by competitive ELISA using a polyclonal rabbit antisera raised against AGE-RNase.

Results. Diabetic subjects were subdivided into three groups (normoalbuminuria, microalbuminuria and proteinuria). Serum AGEs were significantly increased in diabetic patients with microalbuminuria or proteinuria (P < 0.001). Cholesterol efflux was significantly decreased in all three groups of diabetic patients compared to controls (P < 0.001) whereas the antioxidative capacity of HDL was significantly impaired in patients with microalbuminuria or proteinuria (P < 0.01). No relationship between serum AGEs and cholesterol efflux was found. However, serum AGE concentration was significantly associated with the antioxidative capacity of HDL and this was partly due to the adverse effect of AGEs on paraoxonase-1 activity.

Conclusion. In type 2 diabetic patients with incipient or overt nephropathy, increased serum concentration of AGEs was associated with impairment in the antioxidative capacity of HDL. Cholesterol efflux to serum was also reduced but was not related to serum AGEs.

Keywords: advanced glycation end products; cholesterol efflux; diabetic nephropathy; HDL; type 2 diabetes mellitus



   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Advanced glycation end products (AGEs) are a heterogeneous group of proteins and lipids to which sugar residues are covalently bound and these compounds have been implicated in the pathogenesis of many of the complications of diabetes. Formation of AGEs is enhanced by hyperglycaemia and is also stimulated by oxidative stress [1,2]. Increased circulating and tissue AGEs have been demonstrated in both animal and human studies of diabetes mellitus [3], and elevated concentrations of serum AGEs have been reported in children and adults with diabetes [4,5]. The increase in serum AGE concentration is most marked in diabetic subjects with end-stage renal disease as the removal of AGEs and their degradative products are known to depend on renal clearance [6,7]. The binding of AGEs to their cellular receptors plays an important role in the development of diabetic vascular complications. AGEs can cause a number of adverse cellular events, including reduction of enzymatic activity, damage to nucleic acids, cross-linking and impaired degradation of proteins and induction of cytotoxic pathways [1–3,8].

In addition to these detrimental effects of AGEs, there is recent evidence to suggest that AGEs may also interfere with the function of HDL and the reverse cholesterol transport pathway. It has recently been reported that the reduction in paraoxonase-1 (PON-1) activity, an antioxidant protective enzyme known to be physically associated with HDL, in patients with end-stage renal disease is partly due to the increase in serum AGEs. PON-1 activity improves after haemodialysis and the clearance of low molecular weight AGEs is shown to be the main determinant of the improvement in PON-1 activity, suggesting that AGEs, at least in part, participates in the loss of PON-1 activity [9]. Hence, circulating AGEs may potentially cause HDL dysfunction by impairing the antioxidative capacity of HDL. AGEs may also inhibit reverse cholesterol transport. Scavenger receptor class B type 1 (SR-BI) is an HDL receptor that mediates the selective uptake of HDL cholesteryl esters into cells and also facilitates the efflux of cholesterol from cells to HDL. It has been shown that AGEs, acting as ligands for SR-B1, inhibit both SR-B1 mediated selective uptake of HDL cholesteryl ester and cholesterol efflux from peripheral cells to HDL in vitro [10]. Since the concentration of circulating AGEs is increased in patients with diabetes, we have investigated whether serum level of AGEs is associated with impairment in the antioxidative capacity of HDL and in the ability of serum to induce cholesterol efflux mediated by SR-B1 in type 2 diabetic patients with and without nephropathy.



   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Type 2 diabetic patients were recruited from the diabetes clinics at Queen Mary Hospital and patients on insulin therapy were eligible if they had been previously managed with diet and an oral agent at some point and had no known history of diabetic ketoacidosis. Diabetic patients were invited to participate when they attended their annual screening visit for diabetic complications and were divided into those with normoalbuminuria (<30 mg/day), microalbuminuria (30–300 mg/day) and proteinuria (>300 mg/day) according to their urinary albumin excretion rate. Macrovascular disease was defined as evidence of ischaemic heart disease (according to clinical history and Minnesota coding of ECG), stroke, transient ischaemic attack or peripheral vascular disease. Diagnosis of retinopathy was based on fundoscopic finding by ophthalmoscopy. One hundred and sixty-seven healthy age-matched controls were recruited from the community. Fasting blood samples were taken for the measurement of glucose, lipids, HbA1c, C-reactive protein (CRP) and serum AGEs, HDL antioxidative capacity and cholesterol efflux. The study was approved by the Ethics Committee of the University of Hong Kong and informed consent was obtained from all subjects.

Serum AGEs were measured by competitive enzyme-linked immunosorbent assay (ELISA) using a well-characterised polyclonal rabbit antisera raised against AGE-RNase [5]. In brief, 96-well plates were coated with 50 µl/ well of AGE-RNase (3.75 µg/ml). Fifty microliters of serum (1:4 dilution) was added, followed by 50 µl of 1:500 diluted anti-AGE antibody. Alkaline phosphate-conjugated anti-rabbit IgG (1:2000) in dilution buffer was then added to each well and incubated for 1 h at 37°C. After washing, colour was developed by addition of 100 µl pNPP substrate (Sigma). OD at 405 nm was determined by an ELISA reader. Results were calculated as 1 – [(experimental OD – background OD)/(total OD – background OD)] and a 50% competition was defined as 1 unit of AGEs. The interassay coefficient of variation was 7.4%.

Cellular cholesterol efflux to serum was measured as described by Syvaane et al. [11], using Fu5AH rat hepatoma cells (a generous gift from Dr. GH Rothblat) which had a high expression level of SR-B1 and lack functional ATP-binding cassette transporters. Cells were cultured in minimal essential medium (MEM) containing 5% calf serum and labeled with [3H]cholesterol for 48 h (Amersham Biosciences, 1 µCi/well). [3H]cholesterol was then allowed to equilibrate among cellular cholesterol pools by incubating the cells in MEM containing 0.25% BSA for 18 h. After washing the cells with PBS, 5% diluted serum in MEM was added and incubated at 37°C. After 4 h of incubation, medium was removed and the cell monolayer was washed and harvested. Radioactivity was measured in both medium and cells. Cholesterol efflux, expressed as percent, was calculated as the amount of label recovered in the medium divided by the total label in each well. Each assay of cholesterol efflux was performed in triplicate and the interassay coefficient of variation was 8.0%.

HDL antioxidative capacity is determined by measuring the ability of HDL to protect LDL against oxidation and reduce the formation of oxidation products as described [12]. LDL was isolated from one healthy, normolipidaemic male donor by discontinuous density gradient ultracentrifugation using a VTi-65 rotor (Beckman Coulter Inc., Palo Alto, CA, USA) at 65 000 rpm for 1.5 h at 10°C, stored at 4°C under nitrogen and used within 7 days. HDL from subject's plasma sample was isolated by the dextran sulfate method. To determine HDL antioxidative capacity, LDL was incubated in air/saline containing dichlorofluorescein (DCFH) with gentle mixing at room temperature to generate mildly oxidized LDL by itself (control) or in the presence of test HDL sample. Upon interaction with the lipid oxidation products formed, DCFH formed DCF and produced intense fluorescence. The assay was performed by adding LDL (2.5 µg cholesterol) with or without test HDL (1 µg cholesterol) to tubes containing DCFH (20 µg) and the volume was adjusted to 200 µl using normal saline. The tubes were then gently vortexed and incubated at room temperature in the dark. After 2 h of incubation, fluorescence readings were obtained using a Fluostar Optima scanning spectrofluorometer (BMG, Victoria, Australia) set at an excitation wavelength of 485 nm and an emission wavelength of 530 nm. The interassay coefficient of variation was 7.7%.

Plasma high sensitivity CRP was measured by a particle-enhanced immunoturbidimetric assay (Roche Diagnostics, GmbH, Mannheim, Germany) using anti-CRP mouse monoclonal antibodies coupled to latex microparticles. Plasma total cholesterol and triglyceride were determined enzymatically on a Hitachi 912 analyzer (Roche Diagnostics, GmbH, Mannheim, Germany). LDL cholesterol was calculated by the Friedewald equation or measured directly if plasma triglyceride was >4.5 mmol/l. Apolipoproteins (apo) AI and B were measured by rate nephelometry using the Beckman Array System (Beckman Instruments). HbA1c was measured in whole blood using ion-exchange high performance liquid chromatography with the Bio-Rad Variant Haemoglobin Testing System (Bio-Rad Laboratories Inc., CA, USA). PON-1 activity in HDL isolated by the dextran sulfate method was determined by a highly sensitive fluorometric assay (excitation/emission maxima 360/ 450 nm) for the organophosphate activity of PON-1 based on the hydrolysis of a fluorogenic organophosphate analog using EnzChek® Paraoxonase Assay Kit (InvitrogenTM). Urinary albumin excretion rate was determined from the mean of two consecutive 12-h overnight urine collections. Urine albumin was measured by rate nephelometry using the Beckman Array 360 Analyzer (Beckman-Coulter Inc., Fullerton, CA, USA). Glomerular filtration rate was calculated using the formula from the Modification of Diet in Renal Disease Study.

Results are expressed as mean and standard deviation, or as median and interquartile range if the distribution of the data was found to be skewed. Data that were not normally distributed were logarithmically transformed before analyses were made. Chi-square test was used to compare differences in proportions between groups. Analysis of variance (ANOVA) was used to compare continuous variables for multiple groups followed by post-hoc multiple comparisons using Dunnett t-tests with the non-diabetic control as the reference group. Pearson's correlations were used to test the relationship between variables and univariate general linear model was used to assess the relationships between serum AGEs and various variables simultaneously.



   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The clinical characteristics of the controls and diabetic patients are shown in Table 1. The duration of diabetes was similar in the three groups of diabetic patients. The proteinuric patients had more complications, higher blood pressure and a greater proportion of them were receiving insulin therapy, angiotensin converting enzyme inhibitor (ACEI) or angiotensin II receptor antagonist (AIIA). Glycaemic control was comparable in the three groups of diabetic patients (Table 2). Serum AGEs were significantly increased in diabetic patients with microalbuminuria or proteinuria compared to controls whereas in the normoalbuminuric patients, serum AGEs were also higher but did not reach statistical significance on post-hoc analysis. Hypertriglyceridaemia and low HDL was observed in diabetic subjects and plasma apo A1 was reduced. Cholesterol efflux to serum was significantly decreased in all three groups of diabetic patients (ANOVA, P < 0.001) whereas HDL antioxidative capacity was only significantly impaired in patients with microalbuminuria or proteinuria (ANOVA, P < 0.01) (Figure 1A and B). These differences remained significant after excluding those subjects on lipid lowering agents in the analysis, and repeating the analyses after adjusting for age, gender, BMI and smoking did not change our results. Since diabetic subjects are known to have smaller HDL size and HDL was standardised by its cholesterol content in the oxidation protection assay, data were also analysed after normalisation for apo A1 content. HDL antioxidative capacity remained reduced in microalbuminuric and proteinuric subjects (P < 0.05).


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  		Table 1. Clinical characteristics of diabetic patients and controls

 

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  		Table 2. Fasting lipids, serum AGEs, cholesterol efflux and HDL dysfunction in diabetic patients and controls

 

Figure 1
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  		Fig. 1. (A) Cholesterol efflux to serum in diabetic patients and controls. Post-hoc analysis: *P < 0.01, **P < 0.001 vs controls. (B) HDL antioxidative dysfunction determined by measuring the capacity of HDL to prevent the oxidation of LDL ex vivo. Values are mean ± SD. Post-hoc analysis: *P < 0.05 vs controls.

 
On correlation analysis, cholesterol efflux was associated with plasma HDL in the whole group of diabetic patients and in the controls (r = 0.57, P < 0.001 and r = 0.45, P < 0.001, respectively) and with plasma apo AI (r = 0.59, P < 0.001 and r = 0.46, P < 0.001, respectively). Cholesterol efflux also correlated with log(triglyceride) (r = –0.22, P < 0.001), log(creatinine) (r = –0.31, P < 0.001), log(CRP) (r = –0.14, P = 0.02) in the diabetic subjects whereas in controls, cholesterol efflux correlated only with log(triglyceride) (r = –0.27, P < 0.001). No correlation was found between cholesterol efflux and serum AGEs or HbA1c in either the diabetic patients or controls. On the other hand, HDL antioxidative capacity correlated with serum AGEs in the diabetic patients (r = 0.20, P = 0.008) and in controls (r = 0.17, P = 0.03). No correlation was seen with plasma HDL, apo AI, HbA1c, log(creatinine) or log(CRP).

To determine what the important determinants of cholesterol efflux were general linear model univariate analysis was performed. Age, gender, BMI, smoking status, the status of nephropathy, the use of lipid lowering therapy and continuous variables which showed an association with cholesterol efflux were entered into the model and the results are shown in Table 3. Only plasma HDL and the status of nephropathy were significant independent determinants of cholesterol efflux. The analyses were repeated in the diabetic cohort alone and plasma HDL (P < 0.001) remained the main determinant of cholesterol efflux, accounting for approximately one-third of the variation in cholesterol efflux. Table 4 shows the general linear model univariate analysis of HDL antioxidative capacity in all subjects. Serum concentration of AGEs and smoking status were the main determinants of HDL antioxidative capacity and the results were the same when the analysis was repeated in the diabetic cohort.


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  		Table 3. General linear model univariate analysis with cholesterol efflux as the dependent variable

 

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  		Table 4. General linear model univariate analysis with HDL antioxidative capacity as the dependent variable

 
To further investigate the underlying cause of the relationship between serum AGEs and HDL antioxidative capacity, the activity of PON-1 in HDL was determined as it has recently been suggested that AGEs might adversely influence PON-1 activity [9]. Subjects on lipid lowering therapy were excluded as PON-1 can be modulated by lipid lowering agents [13,14] A significant reduction in PON-1 activity was found in the microalbuminuric and proteinuric subjects (Figure 2) and there was an inverse association between serum AGE and PON-1 activity (r = –0.22, P = 0.001) (Figure 3).


Figure 2
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  		Fig. 2. PON-1 activity in diabetic patients and controls. Values are mean ± SD. Post-hoc analysis: * P < 0.05 vs controls.

 

Figure 3
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  		Fig. 3. Correlation between serum AGEs and PON-1 activity.

 


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In the present study, we have examined whether circulating AGEs can interfere with the antioxidative capacity of HDL as well as the ability of serum to induce cellular cholesterol efflux in type 2 diabetic subjects. Using a functional assay, we have demonstrated that HDL isolated from diabetic subjects with microalbuminuria or proteinuria has reduced ability to prevent the oxidation of LDL ex vivo. Although we did not measure oxidised LDL level in our subjects, we and others have previously shown that impairment in the antioxidative capacity of HDL was associated with increase in oxidised LDL level [12,15]. There is an association between serum concentration of AGEs and the antioxidant capacity of HDL in the present study, suggesting that AGEs may have an adverse effect on the antioxidative function of HDL. To investigate the potential underlying mechanism of this association, we have measured PON-1 activity in HDL as Gugliucci et al. have recently shown that the accumulation of low molecular weight AGE adducts in patients with end-stage renal disease was associated with a loss of PON-1 activity [9]. PON-1 is an important antioxidative enzyme in HDL. We have found that PON-1 activity in HDL was decreased in microalbuminuric and proteinuric patients and there was an inverse correlation between AGEs and PON-1 activity. In keeping with the findings of Gugliucci et al., our data suggest that increased AGEs in our diabetic subjects might result in a loss of PON-1 activity leading to impaired antioxidative ability of HDL. How AGEs reduce PON-1 activity warrants further investigation. Another potential mechanism whereby AGEs may impair the antioxidative function of HDL is by increasing oxidative stress. The binding of AGEs to cell surface receptors like the receptor for AGE (RAGE) can stimulate cells to produce reactive oxygen species [16]. This can in turn deplete lipophilic antioxidants carried by HDL, which act as scavengers of oxygen-derived free radicals. Nobecourt et al. have also recently shown that the defective antioxidative activity of small dense HDL3 particles in type 2 diabetes is related to oxidative stress [17]. Although we have not measured oxidative stress in our present study, we and others have reported that increased serum AGEs concentration was associated with elevated levels of markers of oxidative stress in diabetic and non-diabetic subjects [18,19].

In addition to impaired antioxidative function of HDL, we have demonstrated that cellular cholesterol efflux to serum mediated by SR-B1 is also reduced in type 2 diabetic patients but is unrelated to serum AGE concentration. Cellular cholesterol efflux, being the first step in reverse cholesterol transport, plays a very important role in reducing the accumulation of lipids in the arterial wall and prevents the development of atherosclerosis [20]. Efflux of cholesterol from macrophages is particularly important with regard to atherosclerosis and is mediated by lipid transporters/receptors including ATP-cassette transporters and SR-B1 [21]. Many previous studies on cholesterol efflux have used purified acceptor particles such as HDL or lipid-free apolipoproteins and few studies have used whole serum. When whole serum is used, individual variation in factors such as lipoprotein profiles and other serum components that may affect the efficiency of cholesterol efflux can be determined. Using whole serum, therefore, allows us to investigate the impact of circulating AGEs on cholesterol efflux. Cholesterol efflux from Fu5AH cells induced by plasma has been shown to be impaired in diabetic patients with coronary heart disease [11]. We have shown that cellular cholesterol efflux to serum mediated by SR-B1 is reduced in type 2 diabetic patients even in the absence of any diabetic complications and the abnormality is most marked in those with proteinuria. Although AGEs have been shown to be one of the ligands of SR-B1 and can inhibit cholesterol efflux from peripheral cells to HDL in vitro [10], we did not find any association between serum AGE concentration and cholesterol efflux. This would suggest that circulating AGE does not significantly impair cholesterol efflux mediated by SR-B1 in vivo. The major determinant of SR-B1 mediated cholesterol efflux to serum is in fact the concentration of HDL.

Our study has a number of limitations that need to be addressed. Since our study is cross sectional in nature, we can only demonstrate associations and not causal relationships. The functional assay we use determines the protective effect of whole HDL on oxidation of LDL and we did not study individual HDL subpopulations and their composition. We cannot therefore address whether a particular species of HDL particles may account for the reduction in antioxidant effect or the reduction in cellular cholesterol efflux. Only PON-1 activity was determined in our study and we cannot rule out whether AGEs may affect other antioxidant enzymes in HDL. We did not measure specific AGE, but by measuring serum AGEs with a polycloncal antibody, we were able to detect most of the circulating AGEs. We have also only evaluated cellular cholesterol efflux mediated by SR-B1 and we have not investigated cholesterol efflux mediated by the ATP-binding cassette transporters. There are data showing that AGEs can reduce the expression of ATP-binding cassette transporter G1 (ABCG1) expression in macrophages and reduce macrophage cholesterol efflux to HDL in vitro [22].

In conclusion, we have demonstrated that in type 2 diabetic patients with incipient or overt nephropathy, increased serum concentration of AGEs is associated with impairment in the antioxidative capacity of HDL and this was partly due to the adverse effect of AGEs on PON-1 activity. Cholesterol efflux to serum was also reduced, but was not related to serum AGEs.



   Acknowledgments
 
This study is supported by a grant from the Committee on Research and Conference Grants of the University of Hong Kong.

Conflict of interest statement. None declared. The results presented in this paper have not been published previously in whole or part, except in abstract format.



   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Received for publication: 2. 4.07
Accepted in revised form: 20. 8.07


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