The role of fibrin deposition in diabetic glomerulosclerosis: a light, electron and immunofluorescence microscopy study

Farquhar, A.; MacDonald, Mary K.; Ireland, J. T.

doi:10.1136/jcp.25.8.657

Cited by 34 publications

(22 citation statements)

References 29 publications

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“…Indeed, fibrin and mesan- giolysis were observed less commonly in some recent pathologic studies of diabetic nephropathy (3). However, in the older literature, numerous studies demonstrated the activation of intrarenal coagulation as well as fibrin deposition (41,42) in association with mesangiolysis and mesangial nodule formation (42). We believe that this was observed more commonly in the past, before the use of effective antihypertensive agents and better blood sugar control.…”

Section: Discussionmentioning

confidence: 84%

Diabetic Endothelial Nitric Oxide Synthase Knockout Mice Develop Advanced Diabetic Nephropathy

Nakagawa¹,

Sato²,

Glushakova³

et al. 2007

Journal of the American Society of Nephrology

343

347

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The pathogenesis of diabetic nephropathy remains poorly defined, and animal models that represent the human disease have been lacking. It was demonstrated recently that the severe endothelial dysfunction that accompanies a diabetic state may cause an uncoupling of the vascular endothelial growth factor (VEGF)-endothelial nitric oxide (eNO) axis, resulting in increased levels of VEGF and excessive endothelial cell proliferation. It was hypothesized further that VEGF-NO uncoupling could be a major contributory mechanism that leads to diabetic vasculopathy. For testing of this hypothesis, diabetes was induced in eNO synthase knockout mice (eNOS KO) and C57BL6 controls. Diabetic eNOS KO mice developed hypertension, albuminuria, and renal insufficiency with arteriolar hyalinosis, mesangial matrix expansion, mesangiolysis with microaneurysms, and Kimmelstiel-Wilson nodules. Glomerular and peritubular capillaries were increased with endothelial proliferation and VEGF expression. Diabetic eNOS KO mice showed increased mortality at 5 mo. All of the functional and histologic changes were improved with insulin therapy. Inhibition of eNO predisposes mice to classic diabetic nephropathy. The mechanism likely is due to VEGF-NO uncoupling with excessive endothelial cell proliferation coupled with altered autoregulation consequent to the development of preglomerular arteriolar disease. Endothelial dysfunction in human diabetes is common, secondary to effects of glucose, advanced glycation end products, C-reactive protein, uric acid, and oxidants. It was postulated that endothelial dysfunction should predict nephropathy and that correction of the dysfunction may prevent these important complications.

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Section: Discussionmentioning

confidence: 84%

Diabetic Endothelial Nitric Oxide Synthase Knockout Mice Develop Advanced Diabetic Nephropathy

Nakagawa¹,

Sato²,

Glushakova³

et al. 2007

Journal of the American Society of Nephrology

343

347

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show abstract

“…4) They concluded that endothelial and mesangial trapping of fibrinogen and/or other macromolecules might initiate or accelerate mesangial enlargement and irregularities of the basement membrane. In glomerulonephritis, intraglomerular coagulation with fibrin deposition was also suggested to be involved in the development of glomerular injury.…”

Section: Discussionmentioning

confidence: 99%

“…2,3) Also in human and experimental diabetic nephropathy, glomerular fibrin deposition and extracellular matrix (ECM) expansion have been noted. 4,5) In this context, transforming growth factor b (TGF-b) is upregulated in kidney diseases, and TGF-b promotes the production of various ECM proteins. 6) Regarding its relationship with coagulation, thrombin stimulates TGF-b production in mesangial cells in vitro.…”

mentioning

confidence: 99%

Roles of Coagulation Pathway and Factor Xa in the Progression of Diabetic Nephropathy in db/db Mice

Sumi

Yamanaka-Hanada

Bai

et al. 2011

Biological & Pharmaceutical Bulletin

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The active type of coagulation factor X (factor Xa) activates various cell-types through protease-activated receptor 2 (PAR2). We previously reported that a factor Xa inhibitor could suppress Thy-1 nephritis. Considering that fibrin deposition is observed in diabetic nephropathy as well as in glomerulonephritis, this study examined the roles of the coagulation pathway and factor Xa in the development of diabetic nephropathy using type 2 diabetic model mice. Diabetic (db/db) and normoglycemic (m؉/m؉) mice were immunohistochemically evaluated for their expression/deposition of PAR2, transforming growth factor (TGF)-b b, fibrin, extracellular matrix (ECM) proteins, and CD31 at week 20. Significantly greater numbers of PAR2-positive cells and larger amounts of fibronectin, and collagen IV depositions were observed in the glomeruli of db/db mice than those in m؉/m؉ mice. Next, expression of PAR2 versus deposition of collagen IV and fibronectin was compared between week 20 and week 30, and the number of PAR2-positive cells in the glomeruli decreased in contrast with the increased accumulation of ECM proteins. In an intervention study, fondaparinux, a factor Xa inhibitor, was subcutaneously administered for ten weeks from week 10 to 20. Fondaparinux treatment significantly suppressed urinary protein, glomerular hypertrophy, fibrin deposition, expression of connective tissue growth factor, and ECM proteins deposition together with CD31-positive capillaries. These results suggest that coagulation pathway and glomerular PAR2 expression are upregulated in the early phase of diabetes, together with the increase of profibrotic cytokines expression, ECM proteins deposition and CD-31-positive vessels. Factor Xa inhibition may ameliorate glomerular neoangiogenesis and ECM accumulation in diabetic nephropathy.

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“…Fibrin/fibrinogen deposition in the glomeruli is a common feature of diabetic nephropathy [4, 5], suggesting that coagulation activation may be involved in the pathogenesis of diabetic renal disease. Furthermore, several reports claim that diabetes mellitus is associated with changes in the hemostatic system [6,7,8].…”

Section: Introductionmentioning

confidence: 99%

Renal Tissue Factor Expression Is Increased in Streptozotocin-Induced Diabetic Mice

Sommeijer¹,

Florquin²,

Hoedemaker³

et al. 2005

Nephron Exp Nephrol

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Background: Tissue factor (TF) is the key initiator of the coagulation cascade. Recent evidence suggests that TF plays a role in renal fibrin formation and renal failure in experimental kidney disease. We hypothesized that hyperglycemia is an important stimulus of TF expression in the kidney. Methods: Mice were injected with streptozotocin (STZ) (200 mg/kg) or with control buffer. Three or 10 weeks after injection, fibrin, thrombin and TF staining and TF activity were evaluated in the kidney. The effect of hyperglycemia on TF expression and secretion by tubular epithelial cells was measured in vitro. Results: Kidneys of STZ-treated mice showed a marked increase in thrombin staining (3.0 ± 0.5 vs. 1.2 ± 0.11) (p = 0.002) and an increase in TF clotting activity 10 weeks after STZ injection (33.9 ± 1.3 vs. 25.4 ± 1.0 s) (p < 0.0001). Increased glomerular fibrin deposition was present in 3 out of 6 diabetic mice. Tubular cells incubated with D-glucose (25 mmol/l) for 48 h displayed increased cellular TF (p = 0.05). However, soluble TF levels and TF activity in supernatant of cells incubated with D- or L-glucose were not different. Conclusions: These data suggest that hyperglycemia is a causal factor in procoagulant activity associated with diabetic nephropathy.

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The role of fibrin deposition in diabetic glomerulosclerosis: a light, electron and immunofluorescence microscopy study

Abstract: There is much evidence to suggest that the microvasculature in diabetic subjects is hyperpermeable to certain plasma constituents

Cited by 34 publications

References 29 publications

Diabetic Endothelial Nitric Oxide Synthase Knockout Mice Develop Advanced Diabetic Nephropathy

Diabetic Endothelial Nitric Oxide Synthase Knockout Mice Develop Advanced Diabetic Nephropathy

Roles of Coagulation Pathway and Factor Xa in the Progression of Diabetic Nephropathy in db/db Mice

Renal Tissue Factor Expression Is Increased in Streptozotocin-Induced Diabetic Mice

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