Elevation of Soluble Thrombomodulin Antigen Levels in the Serum and Urine of Streptozotocin-Induced Diabetes Model Rats

Nakano, Masahiko; Furutani, Masayuki; Shinno, Hiroyuki; Ikeda, Tomohiro; Oida, Koji; Ishii, Hidemi

doi:10.1016/s0049-3848(00)00216-4

Cited by 11 publications

(6 citation statements)

References 31 publications

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“…Elevated glucose levels and glucose homeostatic dysregulation are the central etiologies in both type 1 and type 2 diabetes (Wertheimer et al, 2001). Increased plasma TM antigen levels are observed in diabetic mice (Nakano et al, 2000). Our previous studies showed that epithelial TM has a pivotal role in keratinocyte differentiation and cutaneous wound healing (Cheng et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Thrombomodulin Promotes Diabetic Wound Healing by Regulating Toll-Like Receptor 4 Expression

Cheng

Lai

Chen

et al. 2015

Journal of Investigative Dermatology

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Keratinocyte-expressed thrombomodulin (TM) and the released soluble TM (sTM) have been demonstrated to promote wound healing. However, the effects of high glucose on TM expression in keratinocytes and the role of TM in diabetic ulcer remain unclear. In this study, we demonstrated that expressions of TM and Toll-like receptor 4 (TLR4) were both downregulated in high-glucose cultured human keratinocytes and in skin keratinocytes of diabetic patients. In addition, the wound-triggered upregulation of TM and sTM production was abolished in both high-glucose cultured human keratinocytes and streptozotocin-induced diabetic mouse skin. Furthermore, supplementation of recombinant sTM could increase TLR4 expression and promote cutaneous wound healing in both high-glucose cultured human keratinocytes and diabetic mice. However, in Tlr4-deleted mice, which exhibited delayed wound healing, the therapeutic benefit of recombinant sTM was abrogated. Moreover, our results showed that tumor necrosis factor-α (TNF-α) expression in keratinocytes was dose-dependently upregulated by glucose, and TNF-α treatment downregulated the expression of TM and TLR4. Taken together, high-glucose environment reduces the expression of TM and TLR4 in keratinocytes possibly through the action of TNF-α, and recombinant sTM can increase the TLR4 expression and promote wound healing under diabetic condition.

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Section: Discussionmentioning

confidence: 99%

Thrombomodulin Promotes Diabetic Wound Healing by Regulating Toll-Like Receptor 4 Expression

Cheng

Lai

Chen

et al. 2015

Journal of Investigative Dermatology

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“…Injured endothelial cells release sTM into the circulation, where it binds thrombin, inhibiting it from forming fibrin and activating platelets. sTM has additional anti-thrombotic activity as a cofactor for the thrombin-catalyzed activation of protein C [ 23 ]. Elevated sTM is associated with lower eGFR in CKD and end stage renal disease ESRD [ 24 , 25 ], and our results extend these findings to a broader spectrum of eGFR.…”

Section: Discussionmentioning

confidence: 99%

Kidney function and multiple hemostatic markers: cross sectional associations in the multi-ethnic study of atherosclerosis

Dubin

Cushman

Folsom³

et al. 2011

BMC Nephrol

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BackgroundDefined as estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2, chronic kidney disease (CKD) is strongly and independently associated with cardiovascular and overall mortality. We hypothesized that reduced kidney function would be characterized by abnormalities of hemostasis.MethodsWe tested cross-sectional associations between (eGFR) and multiple hemostatic markers among 6751 participants representing a broad spectrum of kidney function in the Multi-Ethnic Study of Atherosclerosis (MESA). Kidney function was measured using cystatin C (eGFRcys) or creatinine, using CKD Epidemiology Collaboration (eGFRcr). Hemostatic markers included soluble thrombomodulin (sTM), soluble tissue factor (sTF), D-Dimer, von Willebrand factor (vWF), factor VIII, plasmin-antiplasmin complex (PAP), tissue factor pathway inhibitor (TFPI), plasminogen activator inhibitor-1 (PAI-1), and fibrinogen. Associations were tested using multivariable linear regression with adjustment for demographics and comorbidities.ResultsIn comparison to persons with eGFRcys >90 ml/min/1.73 m2, subjects with eGFRcys < 60 ml/min/1.73 m2 had adjusted levels of sTM, sTF, D-Dimer, PAP, Factor VIII, TFPI, vWF and fibrinogen that were respectively 86%, 68%, 44%, 22%, 17%, 15%, 12% and 6% higher. Subjects with eGFRcys 60-90 ml/min/1.73 m2 had adjusted levels that were respectively 16%, 14%, 12%, 6%, 6%, 6%, 11% and 4% higher (p < 0.05 for all). Percent differences were not significantly different when groups were categorized by eGFRcr.ConclusionsThroughout a broad spectrum of kidney function, lower eGFR was associated with higher levels of hemostatic markers. Dysregulation of hemostasis may be a mechanism by which reduced kidney function promotes higher cardiovascular risk.

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“…Activated protein C is best known for its natural anticoagulant properties. Previous research into endothelial necrosis in diabetes mellitus and collagen vascular diseases has shown that TM is cleaved into soluble fragments by neutrophilic leukocyte esterase and released into serum 11–13 . Plasma thrombomodulin concentrations have been reported to be increased in DM patients 13 .…”

Section: Discussionmentioning

confidence: 99%

“…Previous research into endothelial necrosis in diabetes mellitus and collagen vascular diseases has shown that TM is cleaved into soluble fragments by neutrophilic leukocyte esterase and released into serum. [11][12][13] Plasma thrombomodulin concentrations have been reported to be increased in DM patients. 13 Our results confirmed thatTM is lost from the vascular endothelial cells of DM patients, paralleling capillary necrosis.…”

Section: Discussionmentioning

confidence: 99%

Reduction expression of thrombomodulin and endothelial cell nitric oxide synthase in dermatomyositis

Shen

et al. 2007

Neuropathology

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Dermatomyositis (DM) is a systemic microvasculitis predominantly involving the capillaries. We investigated the expression of thrombomodulin (TM) and endothelial cell nitric oxide synthase (eNOS) in microvessels of DM patients. Twelve patients with acute or subacute onset of proximal muscle weakness and erythematous rash over their faces and shoulders were included in this study. Serum creatine phosphokinase was elevated in almost all patients. Electromyograph showed a myopathic pattern in all patients. Muscle biopsies were performed in all patients and 10 non-DM controls and studied with histological, enzyme histochemical and immunohistochemical staining. von Willebrand factor, TM and eNOS antibodies were used as the primary antibodies. Perifascicular degeneration and inflammatory cell infiltration in the perimysium were noted in almost all patients. Non-special esterase staining was markedly positive in capillary and microvascular endothelium. Marked reduction in TM and eNOS staining was noted in DM patients in perimysium microvessels and perifascicular area capillaries. Vascular lesions in DM were not only limited to capillaries. The low expression of TM and eNOS in microvessels suggests the anticoagulation and vasodilation functions of vascular endothelium is reduced. DM is an inflammatory vascular endothelial disease.

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Elevation of Soluble Thrombomodulin Antigen Levels in the Serum and Urine of Streptozotocin-Induced Diabetes Model Rats

Cited by 11 publications

References 31 publications

Thrombomodulin Promotes Diabetic Wound Healing by Regulating Toll-Like Receptor 4 Expression

Thrombomodulin Promotes Diabetic Wound Healing by Regulating Toll-Like Receptor 4 Expression

Kidney function and multiple hemostatic markers: cross sectional associations in the multi-ethnic study of atherosclerosis

Reduction expression of thrombomodulin and endothelial cell nitric oxide synthase in dermatomyositis

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