Renal endothelial protein C receptor expression and shedding in diabetic nephropathy (original) (raw)
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Title Phenotypic expression of ADAMTS 13 in glomerular endothelialcells
2011
Background: ADAMTS13 is the physiological von Willebrand factor (VWF)-cleaving protease. The aim of this study was to examine ADAMTS13 expression in kidneys from ADAMTS13 wild-type (Adamts13) and deficient (Adamts13) mice and to investigate the expression pattern and bioactivity in human glomerular endothelial cells. Methodology/Principal Findings: Immunohistochemistry was performed on kidney sections from ADAMTS13 wild-type and ADAMTS13-deficient mice. Phenotypic differences were examined by ultramorphology. ADAMTS13 expression in human glomerular endothelial cells and dermal microvascular endothelial cells was investigated by real-time PCR, flow cytometry, immunofluorescence and immunoblotting. VWF cleavage was demonstrated by multimer structure analysis and immunoblotting. ADAMTS13 was demonstrated in glomerular endothelial cells in Adamts13 mice but no staining was visible in tissue from Adamts13 mice. Thickening of glomerular capillaries with platelet deposition on the vessel w...
International Journal of Molecular Sciences
Disintegrin and metalloproteinase domain 17 (ADAM17) activates inflammatory and fibrotic processes through the shedding of various molecules such as Tumor Necrosis Factor-α (TNF-α) or Transforming Growht Factor-α (TGF-α). There is a well-recognised link between TNF-α, obesity, inflammation, and diabetes. In physiological situations, ADAM17 is expressed mainly in the distal tubular cell while, in renal damage, its expression increases throughout the kidney including the endothelium. The aim of this study was to characterize, for the first time, an experimental mouse model fed a high-fat diet (HFD) with a specific deletion of Adam17 in endothelial cells and to analyse the effects on different renal structures. Endothelial Adam17 knockout male mice and their controls were fed a high-fat diet, to induce obesity, or standard rodent chow, for 22 weeks. Glucose tolerance, urinary albumin-to-creatinine ratio, renal histology, macrophage infiltration, and galectin-3 levels were evaluated. Re...
Phenotypic Expression of ADAMTS13 in Glomerular Endothelial Cells
PLoS ONE, 2011
Background: ADAMTS13 is the physiological von Willebrand factor (VWF)-cleaving protease. The aim of this study was to examine ADAMTS13 expression in kidneys from ADAMTS13 wild-type (Adamts13 +/+) and deficient (Adamts13 2/2) mice and to investigate the expression pattern and bioactivity in human glomerular endothelial cells. Methodology/Principal Findings: Immunohistochemistry was performed on kidney sections from ADAMTS13 wild-type and ADAMTS13-deficient mice. Phenotypic differences were examined by ultramorphology. ADAMTS13 expression in human glomerular endothelial cells and dermal microvascular endothelial cells was investigated by real-time PCR, flow cytometry, immunofluorescence and immunoblotting. VWF cleavage was demonstrated by multimer structure analysis and immunoblotting. ADAMTS13 was demonstrated in glomerular endothelial cells in Adamts13 +/+ mice but no staining was visible in tissue from Adamts13 2/2 mice. Thickening of glomerular capillaries with platelet deposition on the vessel wall was detected in Adamts13 2/2 mice. ADAMTS13 mRNA and protein were detected in both human endothelial cells and the protease was secreted. ADAMTS13 activity was demonstrated in glomerular endothelial cells as cleavage of VWF. Conclusions/Significance: Glomerular endothelial cells express and secrete ADAMTS13. The proteolytic activity could have a protective effect preventing deposition of platelets along capillary lumina under the conditions of high shear stress present in glomerular capillaries.
Endothelial cell-selective adhesion molecule in diabetic nephropathy
European Journal of Clinical Investigation, 2012
Background Endothelial cell-selective adhesion molecule (ESAM) contributes to the integrity of tight junctions and modulates endothelial function. ESAM has been linked to experimental diabetic nephropathy; its soluble fraction is related to atherosclerosis in humans. In this cross-sectional observational study, we describe for the first time serum ESAM in type 2 diabetic patients with different stages of chronic kidney disease (CKD) and its relationship to vascular endothelial growth factor-A (VEGF-A). Materials and methods We included diabetic patients with different stages of CKD and controls. History, laboratory evaluation, serum ESAM and VEGF-A and urinary albumin ⁄ creatinine ratio were obtained. Results Endothelial cell-selective adhesion molecule was higher in non-CKD diabetic patients 13AE80 (6AE15-18AE70) ng ⁄ mL (n = 45) than controls 7AE30 (4AE60-9AE40) ng ⁄ mL (n = 48), P = 0AE001. VEGF-A had a similar pattern: 71AE3 (54AE75-120AE70) vs. 43AE20 (30AE1-65AE90) pg ⁄ mL, P < 0AE0001. ESAM was 10AE4 (5AE6-17AE4) ng ⁄ mL in predialysis CKD patients (n = 59) and 22AE35 (8AE55-29AE95) ng ⁄ mL in dialysis patients (n = 36), P < 0AE001. Patients with glomerular filtration rate (GFR) < 15 mL ⁄ min had the highest ESAM (P = 0AE003). ESAM was similar in normoalbuminuric, microalbuminuric and proteinuric patients. ESAM was directly correlated with the duration of diabetes (r 2 = 0AE048, P = 0AE009), C-reactive protein (r 2 = 0AE028, P = 0AE05), VEGF-A (r 2 = 0AE040, P = 0AE01) and inversely with HbA1C (r 2 = 0AE036, P = 0AE03), haemoglobin (r 2 = 0AE062, P = 0AE005) and albumin (r 2 = 0AE0AE40, P = 0AE026). In multiple regression diabetes duration, HbA1C and VEGF-A were significant predictors of ESAM. In controls, ESAM was inversely related to VEGF (r 2 = 037, P = 0AE01). Conclusion Endothelial cell-selective adhesion molecule and VEGF-A are higher in patients with diabetes than in controls. The highest ESAM is found in dialysis patients. ESAM correlates with diabetes duration and control, inflammation and VEGF-A in patients with diabetes, but not in controls.
The Missing Link in Diabetic Nephropathy?
2010
Proinsulin C-peptide has been found to exert beneficial effects in many tissues affected by diabetic microvascular complications, including the kidneys. Glomerular hyperfiltration and microalbuminuria are early markers of diabetic nephropathy. C-peptide at physiological concentrations effectively reduces diabetes-induced glomerular hyperfiltration via constriction of the afferent arteriole, dilation of the efferent arteriole, and inhibition of tubular reabsorption in experimental models of type 1 diabetes. The glomerular hypertrophy and mesangial matrix expansion seen in early diabetes can be reduced or prevented by C-peptide administration, possibly via interference with TGF-β1 and TNFα signaling. Several of C-peptide’s reno-protective effects have been confirmed in human studies; reduced glomerular hyperfiltration and diminished urinary albumin excretion have been documented in type 1 diabetes patients receiving replacement doses of C-peptide for periods of up to 3 months. In this...
Renal Endothelial Dysfunction in Diabetic Nephropathy
Cardiovascular & Hematological Disorders-Drug Targets, 2014
Endothelial dysfunction has been posited to play an important role in the pathogenesis of diabetic nephropathy (DN). Due to the heterogeneity of endothelial cells (ECs), it is difficult to generalize about endothelial responses to diabetic stimuli. At present, there are limited techniques fordirectly measuring EC function in vivo, so diagnosis of endothelial disorders still largely depends on indirect assessment of mediators arising from EC injury. In the kidney microcirculation, both afferent and efferent arteries, arterioles and glomerular endothelial cells (GEnC) have all been implicated as targets of diabetic injury. Both hyperglycemia per se, as well as the metabolic consequences of glucose dysregulation, are thought to lead to endothelial cell dysfunction. In this regard, endothelial nitric oxide synthase (eNOS) plays a central role in EC dysfunction. Impaired eNOS activity can occur at numerous levels, including enzyme uncoupling, post-translational modifications, internalization and decreased expression. Reduced nitric oxide (NO) bioavailability exacerbates oxidative stress, further promoting endothelial dysfunction and injury. The injured ECs may then function as active signal transducers of metabolic, hemodynamic and inflammatory factors that modify the function and morphology of the vessel wall and interact with adjacent cells, which may activate a cascade of inflammatory and proliferative and profibrotic responses in progressive DN. Both pharmacological approaches and potential regenerative therapies hold promise for restoration of impaired endothelial cells in diabetic nephropathy.
Kidney international, 2018
Endothelial dysfunction promotes the pathogenesis of diabetic nephropathy (DN), which is considered to be an early event in disease progression. However, the molecular changes associated with glomerular endothelial cell (GEC) injury in early DN are not well defined. Most gene expression studies have relied on the indirect assessment of GEC injury from isolated glomeruli or renal cortices. Here, we present transcriptomic analysis of isolated GECs, using streptozotocin-induced diabetic wildtype (STZ-WT) and diabetic eNOS-null (STZ-eNOS) mice as models of mild and advanced DN, respectively. GECs of both models in comparison to their respective nondiabetic controls showed significant alterations in the regulation of apoptosis, oxidative stress, and proliferation. The extent of these changes was greater in STZ-eNOS than in STZ-WT GECs. Additionally, genes in STZ-eNOS GECs indicated further dysregulation in angiogenesis and epigenetic regulation. Moreover, a biphasic change in the number ...