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NDT Advance Access published online on November 14, 2007
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfm711
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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 Levels of {alpha}-Defensin (-1, -2 and -3) in Type 1 Diabetic Patients with Nephropathy

M. Saraheimo1,2, C. Forsblom1,2, K. Pettersson-Fernholm1,2, A. Flyvbjerg3, P.-H. Groop1,2, J. Frystyk3 and on behalf of the FinnDiane Study Group

1 Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Finland 2 Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Finland 3 Medical Research Laboratories, Clinical Institute & Medical Department M (Diabetes and Endocrinology), Aarhus University, Denmark

Correspondence and offprint requests to: Correspondence and offprint requests to: Per-Henrik Groop, Folkhälsan Research Center, Biomedicum Helsinki (318b), University of Helsinki, Haartmaninkatu 8, PO Box 63, 00014 Helsinki, Finland. Tel: +358-9-191-25459; Fax: +358-9-191-25452; E-mail: per-henrik.groop{at}helsinki.fi



   Abstract
Top
 Abstract
Introduction
 Research design and methods
 Statistical analysis
 Results
 Discussion
 References
 
Objective. Diabetic nephropathy is associated with low-grade inflammation and activation of the complement system. Defensins, as part of the innate immune system, may play a regulatory role in the complement cascade and may also augment the production of proinflammatory cytokines. The aim of this study was therefore to elucidate whether {alpha}-defensin is associated with diabetic nephropathy, low-grade inflammation and lipid profiles.

Research design and methods. Data were obtained from 189 patients with type 1 diabetes selected from the FinnDiane Study. Patients were divided into three groups according to their albumin excretion rate (AER) in three consecutive overnight or 24-h urine collections: normoalbuminuria (AER <20 µg/min or <30 mg/24 h), microalbuminuria (20 <AER <200 µg/min or 30 <AER <300 mg/24 h) and macroalbuminuria (>200 µg/min or >300 mg/24 h). {alpha}-Defensin was determined by a novel, solid-phase radioimmunoassay (RIA) based on a monoclonal antibody, which recognizes {alpha}-defensin isoforms 1–3.

Results. Total serum {alpha}-defensin (-1, -2 and -3) concentrations were higher (P < 0.001) in patients with macroalbuminuria compared to micro- and normoalbuminuria, but no difference was observed between normoalbuminuria and microalbuminuria. In multiple linear regression analysis {alpha}-defensin was associated with systolic blood pressure (P = 0.032), HDL-cholesterol (P = 0.013), total cholesterol (P = 0.008), age (P = 0.001) and estimated glomerular filtration rate (P = 0.001), but not with low-grade inflammatory markers.

Conclusions. Serum {alpha}-defensin (-1, -2 and -3) concentrations are increased in type 1 diabetic patients with diabetic nephropathy.

Keywords: blood lipids; diabetic nephropathy; {alpha}-defensin; low-grade inflammation



   Introduction
Top
 Abstract
 Introduction
Research design and methods
 Statistical analysis
 Results
 Discussion
 References
 
In type 1 diabetes, the presence of nephropathy has been associated with insulin resistance (IR) and low-grade inflammation [1,2]. Activation of the complement system has also been suggested to play a pathogenetic role in diabetic nephropathy [3,4]. Defensins, which are members of the innate immune system, have been suggested to play a role in the regulation of the complement system and to augment the production of pro-inflammatory cytokines [5,6]. Whether the defensins are associated with the development of diabetic complications is not known.

Defensins belong to the anti-microbial peptides of plants, insects and animals. The defensin family consists of small peptides with broad cytotoxic activity against bacteria, fungi, parasites, viruses and host cells. Vertebrate defensins are organized into three classes, {alpha}-, ß- and {theta}-defensins [7]. The role of the defensin family in the human immune system is based on studies of {alpha}- and ß-defensins, since peptide production of known human {theta}-defensin genes has not yet been shown to exist [8].

Serum and plasma {alpha}-defensin levels may be decreased by activated {alpha}2-macroglobulin, a protease inhibitor, which is able to bind to the {alpha}-defensin peptide [9]. Interestingly, patients with diabetes have been shown to present with higher serum {alpha}2-macroglobulin levels compared to healthy controls [10].

{alpha}-Defensins are shown to enhance or inhibit inflammation in many ways. Regarding the complement system, {alpha}-defensin has been shown to either stimulate or suppress the activation of the classical complement pathway [11,12]. {alpha}-Defensin can also stimulate cytokine production of bronchial epithelial cells and modify the inflammation through the regulation of cytokine production in human monocytes and adhesion molecule expression in endothelial cells [13,14]. In addition, {alpha}-defensin has been reported to inhibit the fibrinolytic system and to stimulate the binding of lipoprotein (a) and low-density lipoprotein cholesterol to vascular cells. Thus, {alpha}-defensin may be a link between inflammation and atherosclerosis [15–17].

The aim of the present study was to measure the {alpha}-defensin (-1, -2 and -3) concentrations in type 1 diabetic patients with different stages of diabetic nephropathy, and to examine whether the level of serum {alpha}-defensin is associated with renal function, low-grade inflammatory markers and the blood lipid profile.



   Research design and methods
Top
 Abstract
 Introduction
 Research design and methods
Statistical analysis
 Results
 Discussion
 References
 
Subjects
The study cohort comprised 189 type 1 diabetic patients, who were selected from the ongoing nationwide, multi-centre Finnish Diabetic Nephropathy Study (FinnDiane) and divided into three groups according to their albumin excretion rate (AER) in three consecutive overnight or in the case of already known macroalbuminuria in 24-h urine collections: normoalbuminuria (AER <20 µg/min or <30 mg/24 h), microalbuminuria (20 <AER <200 µg/ min or 30 <AER <300 mg/24 h) and macroalbuminuria (>200 µg/min or >300 mg/24 h).

Type 1 diabetes was defined as an onset of diabetes before the age of 35 years and permanent insulin treatment initiated within 1 year of diagnosis. The patient selection criteria have been described in detail earlier [2]. The ethical committees of all participating centres approved the study protocol. Written informed consent was obtained from each patient and the study was performed in accordance with the Declaration of Helsinki as revised in 2000.

Methods
Data on medication, smoking, cardiovascular status and diabetic complications were registered with a standardized questionnaire, which was completed by the patient's attending physician based upon medical files. Blood pressure [systolic (SBP) and diastolic (DBP)] was measured twice in the sitting position with a mercury sphygmomanometer after a 10 min rest. Height, weight and waist-to-hip ratio (WHR) were recorded, and blood was drawn for the measurements of HbA1c, lipids, creatinine and inflammatory markers [C-reactive protein (CRP) and interleukin 6 (IL-6)].

HbA1c and lipids [total cholesterol, HDL cholesterol and triglycerides (TG)] were measured by enzymatic methods in the local hospitals. Serum creatinine was determined using a modified Jaffe reaction. As a measure of insulin sensitivity we calculated the estimated glucose disposal rate [eGDR = 24.4–12.97*(waist-to-hip ratio)-3.39*(hypertension; yes = 1; no = 0)–0.6*HbA1c] with an equation developed by Williams et al. [18] and adjusted for HbA1c [19]. To define the severity of renal disease, in addition to AER, we estimated the glomerular filtration rate (GFR) by the Cockroft–Gault formula [20]. CRP was measured by radioimmunoassay (RIA), IL-6 by high sensitivity enzyme immunoassay [2].

The plasma level of {alpha}-defensin was determined by a novel, validated in-house, solid-phase RIA based on a monoclonal antibody, which recognizes {alpha}-defensin isoforms 1–3. Ninety-six well-breakable microtitre plates (catalogue number 473768 from Nunc, Roskilde, Denmark) were incubated overnight at 5°C with 4 mg/L anti-mouse IgG (catalogue number M8890 from Sigma Aldrich, Copenhagen, Denmark) dissolved in 15 mmol/L sodium carbonate, 35 mmol/L sodium hydrogen carbonate, pH 9.6. After washing [wash-buffer: 50 mmol/L Tris–HCl, pH 8.0, 0.9% (w/v) NaCl, 0.5% (v/v) Tween 20 and 0.05% (w/v) NaN3], all wells were blocked with 1% (w/v) bovine serum albumin (BSA, Sigma Aldrich, Copenhagen, Denmark) dissolved in 40 mmol/L phosphate buffer, 0.05% (w/v) NaN3, pH 8.0, and incubated for 3 h at room temperature. After washing, all wells were added 50 µL of standard (purified {alpha}-defensin-1, catalogue number D2040 from Sigma-Aldrich, Copenhagen, Denmark) or diluted plasma (1 in 25), 50 µL of 125I-labelled {alpha}-defensin (~10.000 CPM) and 100 µL of a specific monoclonal antibody (200 µg/L), clone DEF 3 (catalogue number T-1034 from BMA, Augst, Switzerland). Iodinated {alpha}-defensin-1 was prepared in-house using the chloramin-T method. All reagents were dissolved in 40 mmol/L phosphate buffer, containing 5.0% (w/v) BSA, 9% (w/v) NaCl and 0.5% (w/v) Tween 20. All samples (standards and unknown samples) were analysed in duplicates with the exception of non-specific binding (NSB) and the 0 standard, which were analysed in quadruplicates. After addition of antigen, tracer and antibody the microtiter plates were incubated for 2 days at 5°C, washed three times, and counted in a gamma counter for 5 min.

{alpha}-Defensin standards were made by serial dilution and ranged from 1 to 250 µg/L, and serum as well as plasma diluted in parallel with the standard curve (data not shown). The NSB averaged 80 CPM, whereas the signals of the lowest and highest standards averaged ~2400 and ~400 CPM, respectively. Half-maximal binding occurred at a standard concentration of ~100 µg/L. The lower detection limit was estimated to <1.95 µg/L (NSB + 3SD). Mean within assay coefficient of variation (CV) of standards and samples was <6%. The in-between assay CV was estimated by repetitive analysis of a control sample and averaged 9% (seven assays).

The recovery of exogenous {alpha}-defensin-1 was studied in EDTA plasma. A preparation of {alpha}-defensin (100 µL, 500 µg/L) dissolved in assay buffer was incubated with an equal volume of EDTA plasma (n = 10), and measured against EDTA plasma added buffer without {alpha}-defensin. Before assay, all samples were incubated at 5°C overnight to allow binding of {alpha}-defensin standards to plasma proteins. All samples were assayed in two dilutions, 1:10 and 1:20. The recovery averaged 106 ± 7% (range 94–116%) and 106 ± 7% (range 98–119%) after a dilution of 1:20 and 1:10, respectively.

During clotting of blood, {alpha}-defensins are released from the neutrophils and therefore we found it of interest to compare {alpha}-defensin levels in serum and plasma from 14 patients with normoalbuminuria and 14 with macroalbuminuria. For both groups, levels (mean ± SD) were significantly higher (P < 0.001 in normoalbuminuria and P = 0.006 in macroalbuminuria) in serum than plasma (normoalbuminuria: 761 ± 240 versus 380 ± 119 µg/L; macroalbuminuria: 824 ± 262 versus 571 ± 181 µg/L), but levels correlated significantly (r = 0.669 in normoalbuminuria and r = 0.833 in macroalbuminuria) indicating that serum measurements yield valid results. We also studied the effect of repetitive freezing and thawing (nine cycles) on serum and plasma levels of {alpha}-defensin. However, repeated freezing and thawing did not affect the {alpha}-defensin levels (data not shown).



   Statistical analysis
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 Abstract
 Introduction
 Research design and methods
 Statistical analysis
Results
 Discussion
 References
 
Data are expressed as mean ± SD for normally distributed values, as median with range for non-normally distributed values (defensin, TG, creatinine, AER, CRP and IL-6) and percentages. Differences between groups for normally distributed variables were tested using analysis of variance (ANOVA) and nonparametric data with the Kruskal–Wallis test. Frequencies were tested with the Pearson chi-square test or two-tailed Fisher's exact test when appropriate. Correlations were calculated using simple and multiple linear regression analysis. All calculations were performed with SPSS 12.01 (SPSS Inc., Chicago, IL, USA). P-values below 0.05 were considered statistically significant.



   Results
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 Research design and methods
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 Results
Discussion
 References
 
The clinical characteristics of the patients are shown in Table 1. The total serum concentration of {alpha}-defensin (-1, -2 and -3) is shown in Figure 1. Serum {alpha}-defensin levels were higher in diabetic patients with macroalbuminuria compared to micro- and normoalbuminuria (P < 0.001), but no difference was observed between patients with normo- and microalbuminuria.


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  		Table 1. Clinical characteristics of 189 patients with type 1 diabetes

 

Figure 1
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  		Fig. 1. Defensin concentration (µg/L) in all type 1 diabetic patients. Data are median (•) with range ({blacksquare}).

 
The distribution of {alpha}-defensin was not normally distributed and therefore data were logarithmically transformed before being investigated by regression analyses. Univariate correlations between serum total {alpha}-defensin and various clinical variables are shown in Table 2. {alpha}-Defensin correlated positively with WHR, SBP, DBP, HbA1c, total cholesterol, TG, creatinine, AER, CRP and IL-6 and negatively with age, age at onset of diabetes, HDL-cholesterol, eGDR and eGFR. In a multiple linear regression analysis with WHR, SBP, HbA1c, cholesterol, HDL-cholesterol, TG, AER, CRP, IL-6, age and eGFR in the model, defensin was significantly associated with SBP (P = 0.032), HDL-cholesterol (P = 0.013), cholesterol (P = 0.008), age (P = 0.001) and eGFR (P = 0.001) (Table 3).


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  		Table 2. Univariate correlations between total serum {alpha}-defensin [ln {alpha}-defensin (-1, -2 and -3)] and various clinical and laboratory variables.

 

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  		Table 3. Multiple linear regression analysis with ln{alpha}-defensin as the dependent variable

 


   Discussion
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 Abstract
 Introduction
 Research design and methods
 Statistical analysis
 Results
 Discussion
References
 
We report an association of {alpha}-defensin (-1, -2 and -3) with diabetic nephropathy in type 1 diabetic patients, which is a novel observation. There was no independent relationship between {alpha}-defensin and markers of low-grade inflammation, whereas total cholesterol and SBP were positively associated and HDL-cholesterol negatively associated with {alpha}-defensin concentrations. In addition, {alpha}-defensin was inversely associated with age.

{alpha}-Defensin was significantly higher in patients with macroalbuminuria compared to either normo- or microalbuminuria, whereas we could not observe a difference in {alpha}-defensin levels between the two latter groups. In accordance, there was an independent relationship between estimated GFR (Cockcroft–Gault) and {alpha}-defensin suggesting an impact of kidney function on circulating {alpha}-defensin levels. This suggestion is supported by earlier observations that patients with diabetic nephropathy have a decreased ability to degrade peptide hormones [21,22]. The finding that an independent relationship was observed between age and {alpha}-defensin is in line with the known age-related decline in GFR.

An association was observed between {alpha}-defensin and inflammatory markers (CRP and IL-6) in the univariate association, but we could not confirm this in the multivariate analysis. Nor was there any association between {alpha}-defensin and mannose-binding lectin (data not shown), even if chronic inflammation and the lectin pathway have both been associated with diabetic nephropathy, but also suggested to play a role in the pathogenesis of diabetic nephropathy [2,3,4,23]. Thus, {alpha}-defensin might be a novel and independent marker of diabetic nephropathy.

Interestingly, there was an independent significant positive relationship between total cholesterol and {alpha}-defensin and also a significant independent negative relationship between HDL-cholesterol and {alpha}-defensin. This observation, together with a previous study showing that {alpha}-defensin has a stimulatory effect on the binding of lipoprotein (a) and low-density lipoprotein to vascular cells, supports the suggestion that {alpha}-defensin may play a role in the pathogenetic processes of atherosclerosis [15,16,17].

An essential question to be answered is why an increased concentration of {alpha}-defensin (-1, -2 and -3) is associated with advanced diabetic nephropathy. The reason may reside in the possible decreased renal degradation of {alpha}-defensin peptides with advanced nephropathy, since the production of {alpha}-defensin has at least not yet been shown to be inducible like the production of ß-defensin-2 and -3 by inflammatory mediators [24], albeit the expression of {alpha}-defensin in the neutrophils can be increased by G-CSF [25].

In conclusion, serum {alpha}-defensin (-1, -2, and -3) concentrations are increased in type 1 diabetic patients with diabetic nephropathy as compared to patients with either normo- or microalbuminuria. Whether the elevation in serum {alpha}-defensin is pathogenetically related to the development of diabetic nephropathy, or simply reflects changes in function needs to be resolved in further studies.



   Acknowledgments
 
This study was supported by grants from the Danish Research Council for Health and Disease (to J.F. and A.F.), the Danish Diabetes Association (to J.F.) and the Helga and Peter Kornings Foundation (to J.F.). The authors wish to thank Lone Svendsen for expert technical assistance in the measurement of {alpha}-defensin. The FinnDiane Study was supported by grants from the Folkhälsan Research Foundation, Wilhelm and Else Stockmann Foundation, Liv och Hälsa Foundation and the Finnish Medical Society (Finska Läkaresällskapet). The skilled technical assistance of Anna Sandelin and Sinikka Lindh is gratefully acknowledged. Finally, the authors acknowledge all the physicians and nurses at each centre participating in the collection of patients: Central Finland Central Hospital: A. Halonen, A. Koistinen, P. Koskiaho, M. Laukkanen, J. Saltevo and M. Tiihonen; Central Hospital of Kanta-Hame: P. Kinnunen, A. Orvola, T. Salonen and A. Vähänen; Central Hospital of Kymenlaakso: R. Paldanius, M. Riihelä and L. Ryysy; Central Hospital of Lansi-Pohja: P. Nyländen and A. Sademies; Central Ostrobothnian Hospital District: S. Anderson, B. Asplund, U. Byskata and T. Virkkala; City of Vantaa Health Center (Rekola): M. Eerola and E. Jatkola; (Tikkurila): R. Lönnblad, J. Mäkelä, A. Malm and E. Rautamo; Helsinki University Central Hospital (Department of Medicine, Division of Nephrology): K. Pettersson-Fernholm, H. Rosvall, M. Rosengård-Bärlund, M. Rönnback and J. Wadén; Iisalmi Hospital: E. Toivanen; Kainuu Central Hospital: S. Jokelainen, P. Kemppainen, A.-M. Mankinen and M. Sankari; Kerava Health Center: H. Stuckey and P. Suominen; Kouvola Health Center: E. Koskinen and T. Siitonen; Kuopio University Hospital: M. Laakso, L. Niskanen, I. Vauhkonen, T. Lakka, E. Voutilainen, L. Mykkänen, P. Karhapää, E. Lampainen and E. Huttunen; Kuusamo Health Center: E.Vierimaa, E. Isopoussu and H. Suvanto; Kuusankoski Hospital: E. Kilkki and L. Riihelä; Lapland Central Hospital: L. Hyvärinen, S. Severinkangas and T. Tulokas; Länsi-Uusimaa Hospital, Tammisaari: J. Rinne and I.-M. Jousmaa; Mikkeli Central Hospital: A. Gynther, R. Manninen, P. Nironen, M. Salminen and T. Vänttinen; North Karelian Hospital: U.-M. Henttula, P. Kekäläinen, A. Rissanen and M. Voutilainen; Paijat-Hame Central Hospital: H. Haapamäki, A. Helanterä and H. Miettinen; Palokka-Vaajakoski Health Center: P. Sopanen, L. Welling and K. Mäkinen; Pori City Hospital: K. Sävelä, P. Ahonen and P. Merensalo; Riihimäki Hospital: L. Juurinen and E. Immonen; Salo Hospital: J. Lapinleimu, M. Virtanen, P. Rautio and A. Alanko; Satakunta Central Hospital: M. Juhola, P. Kunelius, M-L. Lahdenmäki, P. Pääkköen and M. Rautavirta; Savonlinna Central Hospital: T. Pulli, P. Sallinen, H. Valtonen and A. Vartia; Seinajoki Central Hospital: E. Korpi-Hyövälti, T. Latvala and E. Leijala; South Karelia Hospital District: E. Hussi, T. Hotti, R. Härkönen and U. Nyholm; Tampere University Hospital: I. Ala-Houhala, T. Kuningas, P. Lampinen, M. Määttä, H. Oksala, T. Oksanen, K. Salonen, H. Tauriainen and S. Tulokas; Turku Health Center: I. Hämäläinen, H. Virtamo and M. Vähätalo; Turku University Central Hospital: M. Asola, K. Breitholz, R. Eskola, K. Metsärinne, U. Pietilä, P. Saarinen, R. Tuominen and S. Äyräpää; Vasa Central Hospital: S. Bergkulla, U. Hautamäki, V.-A. Myllyniemi and I. Rusk.

Conflict of interest statement: None of the authors had any conflict of interest with the present study.



   References
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 Abstract
 Introduction
 Research design and methods
 Statistical analysis
 Results
 Discussion
 References
 

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Received for publication: 27. 4.07
Accepted in revised form: 12. 9.07


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