Thrombomodulin Deficiency in Human Diabetic Nerve Microvasculature

Hafer‐Macko, Charlene E.; Ivey, Frederick M.; Gyure, Kymberly A.; Sorkin, John D.; Macko, Richard F.

doi:10.2337/diabetes.51.6.1957

Cited by 31 publications

(20 citation statements)

References 37 publications

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“…58 It has been reported that plasma thrombomodulin from the endothelium caused by reduction of APC are increased in diabetic patients, and the impairment of the thrombomodulin/protein C system is associated with DN. 59 Isermann et al 60 recently reported that APC may delay the onset of nephropathy in long-term experimental diabetes by modulating apoptosis of endothelial cells and podocytes.…”

Section: Neutralizing Agents Against Hyperglycemia’s Toxic Metabolitesmentioning

confidence: 99%

Implications of Treatment That Target Protective Mechanisms Against Diabetic Nephropathy

Mima

King

2012

Seminars in Nephrology

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Summary Diabetes results in vascular changes and dysfunction, and vascular complications are the leading cause of morbidity and mortality in diabetic patients. There has been a continual increase in the number of diabetic nephropathy patients and epidemic increases in the number of patients progressing to end-stage renal diseases. To identify targets for therapeutic intervention, most studies have focused on understanding how abnormal levels of glucose metabolites cause diabetic nephropathy, which is of paramount importance in devising strategies to combat the development and progression of diabetic nephropathy. However, less studied than the systemic toxic mechanisms, hyperglycemia and dyslipidemia might inhibit the endogenous vascular protective factors such as insulin, vascular endothelial growth factor, and platelet-derived growth factor. In this review, we highlight the importance of enhancing endogenous protective factors to prevent or delay diabetic nephropathy.

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Section: Neutralizing Agents Against Hyperglycemia’s Toxic Metabolitesmentioning

confidence: 99%

Implications of Treatment That Target Protective Mechanisms Against Diabetic Nephropathy

Mima

King

2012

Seminars in Nephrology

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“…Alternatively, NF-κB activation in cells of the vessel wall of the vasa nervorum could lead to vascular dysfunction, and, subsequently, to neuronal dysfunction. An association between microangiopathy and neuropathy has long been considered (2,6,10,45), and the AGE-RAGE axis could be one mechanism by which vascular changes ultimately lead to neuronal damage. This interpretation is supported by the observation that the colocalization of CML, RAGE, NF-κB, and IL-6 was restricted to epineurial vessels, perineurium, and endoneurial vessels (Figure 1), while axons from both patients with diabetes and nondiabetic controls were negative for each of the 4 antigens.…”

Section: Figurementioning

confidence: 99%

Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily

Bierhaus

Haslbeck²,

Humpert³

et al. 2004

J. Clin. Invest.

263

190

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Molecular events that result in loss of pain perception are poorly understood in diabetic neuropathy. Our results show that the receptor for advanced glycation end products (RAGE), a receptor associated with sustained NF-κB activation in the diabetic microenvironment, has a central role in sensory neuronal dysfunction. In sural nerve biopsies, ligands of RAGE, the receptor itself, activated NF-κBp65, and IL-6 colocalized in the microvasculature of patients with diabetic neuropathy. Activation of NF-κB and NF-κB-dependent gene expression was upregulated in peripheral nerves of diabetic mice, induced by advanced glycation end products, and prevented by RAGE blockade. NF-κB activation was blunted in RAGE-null (RAGE -/-) mice compared with robust enhancement in strain-matched controls, even 6 months after diabetes induction. Loss of pain perception, indicative of long-standing diabetic neuropathy, was reversed in WT mice treated with soluble RAGE. Most importantly, loss of pain perception was largely prevented in RAGE -/-mice, although they were not protected from diabetes-induced loss of PGP9.5-positive plantar nerve fibers. These data demonstrate, for the first time to our knowledge, that the RAGE-NF-κB axis operates in diabetic neuropathy, by mediating functional sensory deficits, and that its inhibition may provide new therapeutic approaches.

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“…In particular, augmented synthesis of factor VII, thrombin, tissue factor and PAI-1 is detected in the diabetic patient, while anticoagulative substances, such as thrombomodulin and protein C, are diminished [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

C-peptide exerts antithrombotic effects that are repressed by insulin in normal and diabetic mice

et al. 2006

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Aims/hypothesis: Diabetic macro-and microangiopathy are associated with a high risk of vascular complications. The diabetic patient exhibits a pathological coagulation state, with an increased synthesis of coagulation factors and plasminogen activator inhibitor 1 (PAI-1) as well as an enhanced aggregation of platelets. Previous studies have shown that C-peptide can reduce leucocyteendothelial cell interaction and improve microvascular blood flow in patients with type 1 diabetes. In the present study, we examined in vivo whether C-peptide is able to reduce platelet activation and through that microvascular thrombus formation. Materials and methods: In the microvessels of cremaster muscle preparations taken from normal and diabetic mice, ferric chloride-induced thrombus formation was analysed using intravital fluorescence microscopy. Results: I.V. administration of C-peptide in high dose (70 nmol/kg), but not in low dose (7 nmol/kg), caused a significant delay in arteriolar and venular thrombus growth in normal and diabetic mice. This effect was repressed by cremaster muscle superfusion with insulin (100 μU/ml) in diabetic animals, but particularly in normal animals. In parallel, immunohistochemistry demonstrated a higher number of PAI-1-expressing vessels in cremaster muscle tissue from control animals and from animals treated with C-peptide and insulin compared with tissue from animals with C-peptide treatment application alone. Conclusions/interpretation: We conclude that C-peptide possesses antithrombotic actions in vivo. A causal role of PAI-1 in this scenario needs to be further addressed. However, the reversal of C-peptide action by insulin may invalidate the use of this peptide as a treatment option to improve rheology and microcirculation in diabetic patients.

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Thrombomodulin Deficiency in Human Diabetic Nerve Microvasculature

Cited by 31 publications

References 37 publications

Implications of Treatment That Target Protective Mechanisms Against Diabetic Nephropathy

Implications of Treatment That Target Protective Mechanisms Against Diabetic Nephropathy

Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily

C-peptide exerts antithrombotic effects that are repressed by insulin in normal and diabetic mice

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