Endothelial injury is closely related to osteopontin and TNF receptor-mediated inflammation in end-stage renal disease

doi:10.1016/j.cyto.2019.05.016

Cytokine

Volume 121, September 2019, 154729

https://doi.org/10.1016/j.cyto.2019.05.016 Get rights and content

Highlights

•
sTM is a multifunctional molecule released following endothelial injury.
•
sTM may be closely related to TNF-mediated inflammation in ESRD.
•
OPN independently predicts sTM concentrations and may be involved in associated tissue remodeling and mineralization processes.
•
sTM correlates with progression of MAC.
•
sTM does not correlate with age and other traditional CV risk factors.

Abstract

Background

Endothelial dysfunction, inflammation and active mineralization are key processes involved in cardiovascular burden in end stage renal disease (ESRD). Serum (soluble) thrombomodulin (sTM) is an established marker of endothelial injury.

Patients

80 patients in ESRD were recruited consecutively. Baseline distribution of sex, age, main comorbidities and Framingham score was similar. A biochemical panel including sTM, intact PTH (iPTH), interleukin-6 (IL-6), pentraxin 3 (PTX3), fibroblast growth factor 23 (FGF-23), osteopontin (OPN), osteoprotegerin (OPG), osteocalcin (OC), osteonectin (ON), soluble tumor necrosis factor receptor type 2 (TNFR2), transforming growth factor-β (TGF-β), hepatocyte growth factor (HGF), vascular endothelial growth factor receptor type 2 (sVEGFR2) and stromal cell-derived factor 1α (SDF1α) was investigated in each patient. Samples obtained while establishing haemodialysis (HD) access were stained for radial artery calcifications (RACs) with Alizarin red and examined histologically.

Results

After adjustment for HD status, sTM showed a significant positive correlation with serum creatinine, TNFR2, OPN, HGF, SDF1α, sVEGFR2, Pi, iPTH, FGF-23, OPG, OC and ON. In forward stepwise multiple regression, serum creatinine, TNFR2, and OPN were identified as significant, independent predictors of sTM. Grades 1–3 of RACs correlated with sTM (R = 0.50, p = 0.017), while grade 3 RACs were significantly associated with higher sTM (p = 0.02) than less advanced lesions.

Conclusion

Among novel renal and cardiovascular biomarkers, OPN and TNFR2 are closely related to sTM. This may link endothelial damage, vascular remodeling and inflammation. Progression of RAC parallels a presumed compensatory rise in sTM, reflecting endothelial injury. sTM has an intricate role in endothelial function and potential clinical and prognostic applications.

Introduction

In atherosclerotic lesions, the expression of thrombomodulin (TM), a cell membrane glycoprotein, has been demonstrated on the surface of endothelium, intimal and medial smooth muscle cells (SMC) and macrophages. The expression of TM in SMC depended on lesion type and patient age [1]. A soluble form of TM (sTM) is released from endothelial cells in response to endothelial damage [2], or TNFα-stimulated inflammatory settings [3]. TNFα was previously shown to display cytotoxic effects on microvascular endothelium [4], whereas serum TM has been correlated with measures of microvascular dysfunction [5]. Transgenic mice with endothelial TNFα expression, designed to represent chronic endothelial activation, developed inflammation which improved after exogenous sTM treatment [6]. The Atherosis Risk in Communities (ARIC) study revealed that incidence of coronary heart disease in healthy individuals was inversely correlated with sTM [7]. It was suggested that anti-coagulant function of TM, as a cofactor of protein C, and modulation of thrombin activity may be responsible for this protective effect. Conversely, incidence of carotid atherosclerosis was higher in the group characterized by higher sTM quintiles, which might reflect a compensatory, physiological response to endothelial dysfunction and inflammation [7]. Results of the Hoorn study indicate that endothelial dysfunction contributes to cardiovascular (CV) mortality, even in mild renal insufficiency [8]. Indeed, a recent meta-analysis has shown that endothelial function tests are able to significantly predict CV events [9]. In patients with a history of vascular incidents, higher sTM levels have been associated with increased mortality [10]. Elevated sTM in hemodialysis (HD) patients was found to rapidly decline after kidney transplantation, reflecting restoration of the endothelial function [11]. The aim of this study was to assess correlations of sTM with various parameters of cardiovascular and renal pathology in patients with end stage renal disease. In a cross-sectional analysis, we investigated a wide panel of novel biomarkers implicated in cardiovascular comorbidity and chronic kidney disease.

Section snippets

Methods

Eighty patients in stage 5 CKD were consecutively recruited using a convenience sample from the Department of Nephrology, Jagiellonian University Medical College. Patients qualified for hemodialysis (HD) (n = 30) and undergoing HD (n = 50) were included. Following medical examination, blood samples were collected for the panel of laboratory investigations. In patients requiring surgical creation of arteriovenous fistula (AVF) for HD access, radial artery samples were collected for

Pre-dialysis and haemodialysis patient characteristics

The patients did not differ with respect to sex, age, main comorbidities and cardiovascular risk factors. However, serum creatinine concentrations were higher among those under HD, as were the concentrations of the studied inflammatory markers, inorganic phosphate, FGF-23, OPG, OPN and OC. Of note, sTM concentrations were also significantly higher in patients treated with HD (Table 1).

Serum thrombomodulin and traditional cardiovascular risk factors

sTM did not differ between patients with and without diabetes (p = 0.6), hypertension (p = 0.8), hyperlipidemia

Discussion

The salient finding of the present study is that inflammatory and mineralization cytokines TNFR2 and OPN independently predict sTM concentrations. Moreover, medial radial artery calcifications (RAC) closely correlate with sTM levels.

To our knowledge, this is the first study to investigate the relationship between sTM and an extensive panel of novel inflammatory, tissue remodeling and mineral/bone biomarkers in the setting of pre-dialysis and HD.

Previous studies reported that among other

Ethics approval and consent to participate

The study is in accordance with the Declaration of Helsinki and was approved by the Bioethics Committee of the Jagiellonian University. All patients signed an informed consent for participation prior to their inclusion into the study.

Disclosure statement

The manuscript has not been published elsewhere.

Funding

The study was supported by unrestricted grant from the Jagiellonian University Medical College, Cracow, Poland (number K/ZDS/000597).

Authors’ contributions

KB and KK conceived the study, were the major participants in its design, coordination, interpretation of results and statistical analysis, they also prepared draft manuscript. MG carried out histological examinations. PD performed statistical analysis. KW, DF and MK participated in the design of the study. JAL participated in data analysis and in preparation of the final manuscript version. MAK and WS participated in study design and coordination. All authors were involved in data collection,

Declaration of Competing Interest

The authors declare that they have no competing interests.

References (49)

V. Salomaa et al.
Soluble thrombomodulin as a predictor of incident coronary heart disease and symptomless carotid artery atherosclerosis in the Atherosclerosis Risk in Communities (ARIC) Study: a case-cohort study
Lancet
(1999)
A. Shankar et al.
Markers of inflammation predict the long-term risk of developing chronic kidney disease: a population-based cohort study
Kidney Int.
(2011)
R.S. Al-Lamki et al.
TNF receptors: signaling pathways and contribution to renal dysfunction
Kidney Int.
(2015)
D. Venkatesh et al.
Endothelial TNF receptor 2 induces IRF1 transcription factor-dependent interferon-β autocrine signaling to promote monocyte recruitment
Immunity
(2013)
M. Shimizu et al.
Clinical significance of serum soluble TNF receptor II level and soluble TNF receptor II/I ratio as indicators of coronary artery lesion development in Kawasaki disease
Cytokine
(2018)
R. Imamura et al.
Hepatocyte growth factor in physiology and infectious diseases
Cytokine
(2017)
S. Mizuno et al.
Prevention of neutrophil extravasation by hepatocyte growth factor leads to attenuations of tubular apoptosis and renal dysfunction in mouse ischemic kidneys
Am. J. Pathol.
(2005)
T. Shimodaira et al.
Upregulation of osteopontin expression via the interaction of macrophages and fibroblasts under IL-1b stimulation
Cytokine
(2018)
M.M. El-Abbadi et al.
Phosphate feeding induces arterial medial calcification in uremic mice: role of serum phosphorus, fibroblast growth factor-23, and osteopontin
Kidney Int.
(2009)
B.-K. Son et al.
Thrombomodulin, a novel molecule regulating inorganic phosphate-induced vascular smooth muscle cell calcification
J. Mol. Cell. Cardiol.
(2013)

T. Myles et al.

Thrombin activatable fibrinolysis inhibitor, a potential regulator of vascular inflammation

J. Biol. Chem.

(2003)

H. Ikeguchi et al.

Effects of human soluble thrombomodulin on experimental glomerulonephritis

Kidney Int.

(2002)

J. Li et al.

Recombinant thrombomodulin inhibits arterial smooth muscle cell proliferation induced by thrombin

J. Vasc. Surg.

(2000)

Y. Yoshii et al.

Expression of thrombomodulin in human aortic smooth muscle cells with special reference to atherosclerotic lesion types and age differences

Med. Electron Microsc.

(2003)

H. Ishii et al.

Soluble thrombomodulin antigen in conditioned medium is increased by damage of endothelial cells

Thromb. Haemost.

(1991)

M.W. Boehme et al.

Release of thrombomodulin from endothelial cells by concerted action of TNF-alpha and neutrophils: in vivo and in vitro studies

Immunology.

(1996)

Z. Zhou et al.

Role of NF-κB and PI 3-kinase/Akt in TNF-α-induced cytotoxicity in microvascular endothelial cells

Am. J. Physiol. Physiol.

(2008)

K. Igari et al.

The relationship between endothelial dysfunction and endothelial cell markers in peripheral arterial disease

PLoS One

(2016)

G. Rajashekhar et al.

Soluble thrombomodulin reduces inflammation and prevents microalbuminuria induced by chronic endothelial activation in transgenic mice

Am. J. Physiol. Renal Physiol.

(2012)

F. Stam

Endothelial dysfunction contributes to renal function-associated cardiovascular mortality in a population with mild renal insufficiency: the Hoorn study

J. Am. Soc. Nephrol.

(2006)

Y. Matsuzawa et al.

Prognostic value of flow-mediated vasodilation in brachial artery and fingertip artery for cardiovascular events: a systematic review and meta-analysis

J. Am. Heart Assoc.

(2015)

J.-M. Olivot et al.

GENIC investigators, soluble thrombomodulin and brain infarction: case-control and prospective study

Stroke

(2004)

K. Keven et al.

Soluble endothelial cell protein C receptor and thrombomodulin levels after renal transplantation

Int. Urol. Nephrol.

(2010)

K. Janda et al.

Impaired fasting glucose and diabetes as predictors for radial artery calcification in end stage renal disease patients

Int. J. Endocrinol.

(2013)

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This pro-inflammatory environment is also exacerbated by the overexpression of tumour necrosis factor alpha and interleukin 1β, which promote leukocyte migration and adhesion.39 These chemokines induce endothelial cells and leukocytes to express vascular cell adhesion molecules and intercellular adhesion molecules, monocyte chemotactic protein 1, E-selectin and P-selectin, which in turn contribute to the worsening of the ED.40 ED is a multifactorial, early and permanent manifestation of CVD.
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View full text

Endothelial injury is closely related to osteopontin and TNF receptor-mediated inflammation in end-stage renal disease

Highlights

Abstract

Background

Patients

Results

Conclusion

Introduction

Section snippets

Methods

Pre-dialysis and haemodialysis patient characteristics

Serum thrombomodulin and traditional cardiovascular risk factors

Discussion

Ethics approval and consent to participate

Disclosure statement

Funding

Authors’ contributions

Declaration of Competing Interest

Lancet

Kidney Int.

Kidney Int.

Immunity

Cytokine

Cytokine

Am. J. Pathol.

Cytokine

Kidney Int.

J. Mol. Cell. Cardiol.

J. Biol. Chem.

Kidney Int.

J. Vasc. Surg.

Expression of thrombomodulin in human aortic smooth muscle cells with special reference to atherosclerotic lesion types and age differences

Med. Electron Microsc.

Soluble thrombomodulin antigen in conditioned medium is increased by damage of endothelial cells

Thromb. Haemost.

Release of thrombomodulin from endothelial cells by concerted action of TNF-alpha and neutrophils: in vivo and in vitro studies

Immunology.

Role of NF-κB and PI 3-kinase/Akt in TNF-α-induced cytotoxicity in microvascular endothelial cells

Am. J. Physiol. Physiol.

The relationship between endothelial dysfunction and endothelial cell markers in peripheral arterial disease

PLoS One

Soluble thrombomodulin reduces inflammation and prevents microalbuminuria induced by chronic endothelial activation in transgenic mice

Am. J. Physiol. Renal Physiol.

Endothelial dysfunction contributes to renal function-associated cardiovascular mortality in a population with mild renal insufficiency: the Hoorn study

J. Am. Soc. Nephrol.

Prognostic value of flow-mediated vasodilation in brachial artery and fingertip artery for cardiovascular events: a systematic review and meta-analysis

J. Am. Heart Assoc.

GENIC investigators, soluble thrombomodulin and brain infarction: case-control and prospective study

Stroke

Soluble endothelial cell protein C receptor and thrombomodulin levels after renal transplantation

Int. Urol. Nephrol.

Impaired fasting glucose and diabetes as predictors for radial artery calcification in end stage renal disease patients

Int. J. Endocrinol.