Sage Journals: Discover world-class research

Abstract

Introduction

Syndecan (SDC)-1 is a transmembrane heparan sulfate proteoglycan and is a major component of endothelial glycocalyx (EG). This study aimed to investigate the association of serum SDC-1 concentration as a marker of EG degradation with albuminuria in type 2 diabetes.

Methods

We included 370 patients with type 2 diabetes and 219 individuals with no diabetes. The individuals with estimate glomerular filtration rate <30 mL/min/1.73 m² were excluded.

Results

Serum SDC-1 concentration was higher in type 2 diabetes than in no diabetes. The presence of diabetes was independently associated with log [SDC-1] in multivariate analysis. In type 2 diabetes, serum SDC-1 concentration was correlated with log [urinary albumin-to-creatinine ratio (ACR)]. Moreover, log [SDC-1] was an independent determinant of log [ACR] after adjustment for known risk factors of albuminuria.

Conclusions

Serum SDC-1 concentration was higher in patients with type 2 diabetes compared to individuals with no diabetes and an independent determinant of ACR. This study implicates the role of the EG degradation in albuminuria in type 2 diabetes.

Keywords

Albuminuria endothelial glycocalyx syndecan-1 type 2 diabetes

Dear editor,

The endothelial glycocalyx (EG) is a gel-like layer covering vascular endothelial surface and affects glomerular selective permeability.¹ Syndecan-1 (SDC-1) is the main core proteoglycan of EG expressed in vascular endothelial cells.² Serum concentration of SDC-1 is widely used as a biomarker for EG degradation because the extracellular domain of SDC-1 is shed from the endothelial surface when the EG is damaged by various pathological conditions.³ Albuminuria is an important predictor of mortality and the risk of end-stage kidney disease in type 2 diabetes (T2D). Serum SDC-1 levels were increased in various kidney diseases including type 1 diabetes with moderately elevated albuminuria,⁴ however, no studies have examined the relationship between serum SDC-1 levels and the degree of albuminuria in T2D.

This study included 370 patients with T2D who were admitted to the Diabetes Center of Osaka Metropolitan University Hospital and 219 individuals with no diabetes (ND) who underwent comprehensive medical examinations at MedCity21, Osaka Metropolitan University Hospital Advanced Medical Center for Preventive Medicine. Individuals with severe renal failure (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m²) or obvious infectious diseases were excluded for possible influence on circulating SDC-1 concentration.^5,6 Serum SDC-1 concentration was measured in frozen stored samples by enzyme-linked immunosorbent assay kit (Diaclone, Besançon, France).⁶

The mean (SD) age was 60.5 (13.1) years in T2D and 54.9 (12.5) in ND and was significantly different between the groups (p < .001). The median (interquartile range) of urinary albumin to creatinine ratio (ACR) was 12.5 (6.4–39.6) mg/gCr. The percentage users of renin-angiotensin-aldosterone system (RAS) inhibiters was 36.8% in T2D and 7.8% in ND. The median (interquartile range) of serum SDC-1 concentration was 26.3 (18.9–41.6) ng/mL in T2D, which was significantly higher than that in ND (16.0 [9.6–23.5] ng/mL) (p < .001). In univariate analyses, both HbA1c (r = 0.295, p < .001) and fasting plasma glucose (r = 0.183, p < .001) were positively correlated with log [SDC-1]. The independent association was observed between the presence of T2D and log [SDC-1] (β = 0.354, p < .001) in multiple regression analysis after adjustment for age, sex, body mass index, systolic blood pressure, eGFR, low-density lipoprotein (LDL) -cholesterol, complications of cardiovascular diseases, smoking status, use of statins, use of RAS inhibitors, and use of insulin. When the presence of T2D was replaced by fasting plasma glucose or HbA1c, both fasting plasma glucose (β = 0.137, p < .001) and HbA1c (β = 0.229, p < .001) were independently associated with log [SDC-1]. In the analyses limited to T2D, log [SDC-1] was significantly and positively correlated with log [ACR] (r = 0.226, p < .001) in univariate analysis and the association was independent of other covariates (β = 0.117, p = .015) in multiple regression analysis (Table 1).

Table 1.

Multiple regression analysis of the determinants for log [ACR] in type 2 diabetes.

	β	p
Age (years)	−0.355	<.001
Sex (male = 1, female = 0)	−0.040	.410
Duration of diabetes (year)	0.079	.154
Body mass index (kg/m²)	−0.104	.045
Systolic BP (mmHg)	0.369	<.001
Cardiovascular disease (yes = 1, no = 0)	−0.023	.630
Statins (yes = 1, no = 0)	0.113	.018
RAS inhibitors (yes = 1, no = 0)	0.114	.026
Insulin (yes = 1, no = 0)	0.010	.859
Sulfonylureas (yes = 1, no = 0)	0.051	.297
Biguanides (yes = 1, no = 0)	−0.013	.792
DPP-4 inhibitors (yes = 1, no = 0)	−0.034	.473
Smoking (yes = 1, no = 0)	−0.004	.926
eGFR (mL/min/1.73 m²)	−0.244	<.001
HbA1c (%)	0.177	<.001
LDL-C (mg/dL)	0.061	.234
Log [SDC-1 (ng/mL)]	0.117	.015
R² (p)	0.352 (<.001)

Values are standardized regression coefficients (β) determined by using multiple regression analysis. R², coefficient of determination.

Abbreviations: ACR: albumin to creatinine ratio; BP: blood pressure; RAS: renin-angiotensin-aldosterone system; DPP-4: dipeptidyl peptidase-4; eGFR: estimated glomerular filtration rate; HbA1c: glycated hemoglobin A1c; LDL-C: low-density lipoprotein cholesterol; SDC-1: syndecan-1.

This study demonstrated that serum SDC-1 concentration was higher in T2D than ND even after adjustment for various clinical factors Moreover, serum SDC-1 concentration was an independent determinant of ACR after adjustment for known risk factors of microangiopathy and macroangiopathy in T2D such as blood pressure, LDL-cholesterol level, history of cardiovascular diseases and the use of RAS inhibitors and statins. This study with relatively large number of participants with T2D (n = 370) and ND (n = 219) indicates that T2D is independently associated with elevated serum SDC-1 concentration, supporting a previous study with small number of participants with T2D (n = 43) and ND (n = 20).⁷ A previous human study suggested that hyperglycemia exerts an acute toxic effect on the EG via oxidative stress.⁸ Our present study further suggests that chronic hyperglycemia also plays an important role in EG degradation. This study is the first to demonstrate an independent association between serum SDC-1 concentration and the degree of albuminuria in T2D and supports previous studies showing elevated serum SDC-1 concentration in various kidney diseases.^4,9–11 Our findings, coupled with data from previous works, suggest that EG degradation plays an important role in the link between T2D, endothelial dysfunction,^8,12 and albuminuria.^13,14 The present study has several limitations including the cross-sectional design and the potential influence of non-endothelium sources of SDC-1. It also needs to be considered that circulating SDC-1 possibly influences albuminuria via its effect on B-cell differentiation¹⁵ and cell proliferation.¹⁶ In conclusion, serum SDC-1 concentration was higher in T2D compared with ND and was independently associated with ACR. Our data suggest that the EG degradation is involved in the increased renal vascular permeability leading to albuminuria in individuals with T2D.

Footnotes

Acknowledgements

The authors acknowledge the valuable assistance of all the data entry staff at the Department of Metabolism, Endocrinology, and Molecular Medicine, Osaka Metropolitan University Graduate School of Medicine.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Osaka Kidney Foundation (Grant number OKF21-0012); Bayer Academic Support (Grant number BASJ20210415007).

Ethical statement

ORCID iD

Yoshinori Kakutani

References

Becker

Jacob

Leipert

, et al. Degradation of the endothelial glycocalyx in clinical settings: searching for the sheddases. Br J Clin Pharmacol 2015; 80: 389–402. DOI: 10.1111/bcp.12629.

Ballermann

Nystrom

Haraldsson

. The glomerular endothelium restricts albumin filtration. Front Med 2021; 8: 766689. DOI: 10.3389/fmed.2021.766689.

Uchimido

Schmidt

Shapiro

. The glycocalyx: a novel diagnostic and therapeutic target in sepsis. Crit Care 2019; 23: 16. DOI: 10.1186/s13054-018-2292-6.

Svennevig

Kolset

Bangstad

. Increased syndecan-1 in serum is related to early nephropathy in type 1 diabetes mellitus patients. Diabetologia 2006; 49: 2214–2216. DOI: 10.1007/s00125-006-0330-4.

Padberg

Wiesinger

di Marco

, et al. Damage of the endothelial glycocalyx in chronic kidney disease. Atherosclerosis 2014; 234: 335–343. DOI: 10.1016/j.atherosclerosis.2014.03.016.

Piotti

Novelli

Meessen

, et al. Endothelial damage in septic shock patients as evidenced by circulating syndecan-1, sphingosine-1-phosphate and soluble VE-cadherin: a substudy of ALBIOS. Crit Care 2021; 25: 113. DOI: 10.1186/s13054-021-03545-1.

Wang

Guan

Shen

, et al. Insulin increases shedding of syndecan-1 in the serum of patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 2009; 86: 83–88. DOI: 10.1016/j.diabres.2009.08.002.

Nieuwdorp

van Haeften

Gouverneur

, et al. Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo. Diabetes 2006; 55: 480–486. DOI: 10.2337/diabetes.55.02.06.db05-1103.

Chen

Geng

Jin

, et al. The association of syndecan-1, hypercoagulable state and thrombosis and in patients with nephrotic syndrome. Clin Appl Thromb Hemost 2021; 27: 10760296211010256. DOI: 10.1177/10760296211010256.

10.

Kim

Baek

, et al. Elevated serum levels of syndecan-1 are associated with renal involvement in patients with systemic lupus erythematosus. J Rheumatol 2015; 42: 202–209. DOI: 10.3899/jrheum.140568.

11.

Bauer

Piani

Banks

, et al. Minimal change disease is associated with endothelial glycocalyx degradation and endothelial activation. Kidney Int Rep 2022; 7: 797–809. DOI: 10.1016/j.ekir.2021.11.037.

12.

Salmito

de Oliveira Neves

Meneses

, et al. Glycocalyx injury in adults with nephrotic syndrome: association with endothelial function. Clin Chim Acta 2015; 447: 55–58. DOI: 10.1016/j.cca.2015.05.013.

13.

Jawa

Nachimuthu

Pendergrass

, et al. Impaired vascular reactivity in African-American patients with type 2 diabetes mellitus and microalbuminuria or proteinuria despite angiotensin-converting enzyme inhibitor therapy. J Clin Endocrinol Metab 2006; 91: 31–35. DOI: 10.1210/jc.2005-1632.

14.

Kakutani

Morioka

Mori

, et al. Albuminuria rather than glomerular filtration rate is associated with vascular endothelial function in patients with type 2 diabetes. J Diabet Complicat 2020; 34: 107702. DOI: 10.1016/j.jdiacomp.2020.107702.

15.

Liu

Akkoyunlu

. Circulating CD138 enhances disease progression by augmenting autoreactive antibody production in a mouse model of systemic lupus erythematosus. J Biol Chem 2021; 297: 101053. DOI: 10.1016/j.jbc.2021.101053.

16.

Elenius

Gotte

Reizes

, et al. Inhibition by the soluble syndecan-1 ectodomains delays wound repair in mice overexpressing syndecan-1. J Biol Chem 2004; 279: 41928–41935. DOI: 10.1074/jbc.M404506200.

Association of serum syndecan-1 concentrations with albuminuria in type 2 diabetes