Tight Glycemic Control Regulates Fibronectin Expression and Basement Membrane Thickening in Retinal and Glomerular Capillaries of Diabetic Rats
To determine whether tight glycemic control prevents development of basement membrane (BM) thickening in retinal and glomerular capillaries of diabetic rats and whether the extent to which BM thickening develops is linked to fibronectin (FN) overexpression and the degree of hyperglycemia.
Retinal and renal cortical tissues obtained from the tightly controlled diabetic (TC), poorly controlled diabetic (D), and nondiabetic (N) control rats were subjected to morphometric and biochemical analyses. In both tissues, capillary BM thickening was determined by electron microscopy, and FN protein level was assessed by Western blot analysis. Routine measurements of blood glucose level and glycohemoglobin level were performed throughout the study.
The HbA1c level was significantly increased in D rats, but not in TC rats, compared with those of the N rats with a concomitant increase in capillary BM thickness and FN protein expression in retinal and renal tissues. A strong correlation was observed between retinal and glomerular capillary BM thickness (r=0.79, P=0.0001), between retinal and kidney FN protein levels (r=0.7, P=0.005), between HbA1c and FN protein levels in the retina (r=0.66, P=0.006) and kidney (r= .84, P=0.0003), and between HbA1c level and BM thickness in retinal (r=0.76, P=0.0002) and renal tissues (r=0.64, P=0.004).
In diabetes BM thickening develops in retinal and glomerular capillaries in a correlated manner. Tight glycemic control may be beneficial in preventing the pathologic development of capillary BM thickening and FN overexpression in retinal and renal tissues, two target tissues of diabetic microangiopathy.
Available from: sciencedirect.com
- "Vascular BM thickening is the histological hallmark of diabetic retinopathy (Cherian et al., 2009; Lee et al., 2010b; Stitt et al., 1994). The retinal BM in patients with diabetic retinopathy has been described as being irregular and highly vacuolar with a " Swiss cheese " elike appearance (Powner et al., 2011). "
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ABSTRACT: The vascular basement membrane (BM) contains extracellular matrix (ECM) proteins that assemble in a highly organized manner to form a supportive substratum for cell attachment facilitating myriad functions that are vital to cell survival and overall retinal homeostasis. The BM provides a microenvironment in which bidirectional signaling through integrins regulates cell attachment, turnover, and functionality. In diabetic retinopathy, the BM undergoes profound structural and functional changes, and recent studies have brought to light the implications of such changes. Thickened vascular BM in the retinal capillaries actively participate in the development and progression of characteristic changes associated with diabetic retinopathy. High glucose (HG)-induced compromised cell-cell communication via gap junctions (GJ) in retinal vascular cells may disrupt homeostasis in the retinal microenvironment. In this review, the role of altered ECM synthesis, compromised GJ activity, and disturbed retinal homeostasis in the development of retinal vascular lesions in diabetic retinopathy are discussed.
Copyright © 2014. Published by Elsevier Ltd.
Available from: PubMed Central
- "An early functional change associated with the retinal vasculature in diabetic retinopathy is the breakdown of the blood–retinal barrier (BRB) , which is manifested throughout the progression of this ocular complication . The mechanism underlying excess vascular permeability in diabetic retinopathy is not well understood. "
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To determine whether downregulation of Connexin 43 (Cx43) expression promotes development of acellular capillaries (ACs), pericyte loss (PL), excess permeability, and retinal thickening in rat retinas.
Control rats, diabetic rats, and rats intravitreally injected with Cx43 siRNA or scrambled siRNA were used in this study to determine if acute downregulation of Cx43 expression contributes to retinal vascular cell death and excess permeability. Western blot (WB) analysis and Cx43 immunostaining were performed to assess Cx43 protein levels and distribution in the retinal vessels. Concurrently, retinal networks were subjected to terminal deoxynucleotidyl transferase-mediated uridine 5′-triphosphate-biotin nick end labeling (TUNEL) assay and counter-stained to assess the number of apoptotic cells, ACs, and PL. Assessment of fluorescein isothiocyanate-dextran (FITC-dex) extravasation from retinal capillaries and optical coherence tomography (OCT) were performed to determine retinal vascular permeability and retinal thickness, respectively.
WB analysis indicated a significant decrease in the Cx43 protein level in the retinas of the diabetic rats and those intravitreally injected with Cx43 siRNA compared to the retinas of the control rats. Likewise, the retinal vascular cells of the diabetic rats and the Cx43 siRNA-treated rats showed a significant decrease in Cx43 immunostaining. Importantly, the number of apoptotic cells, ACs and PL, FITC-dex extravasation, and thickness increased in the retinas of the diabetic and Cx43 siRNA-treated rats compared to those of the control rats.
Results indicate that downregulation of Cx43 expression alone induces vascular cell death and promotes vascular permeability in the retina. These findings suggest that diabetes-induced downregulation of Cx43 participates in promoting retinal vascular lesions associated with diabetic retinopathy (DR).
Available from: Wayne Orr
- "Hyperglycemia induces thickening of the capillary basement membrane during diabetic retinopathy and nephropathy , and these diabetic basement membranes show enhanced fibronectin deposition as well. Tight glycemic control reduces basement membrane thickening and fibronectin expression in retinal and renal capillaries , suggesting that hyperglycemia drives these changes in matrix composition and structure. Preventing fibronectin expression using locally applied fibronectin siRNA limits microvascular complications of diabetes by reducing basement membrane thickening, acellular capillaries, and pericyte loss  . "
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Altered subendothelial matrix composition regulates endothelial dysfunction and early atherosclerotic plaque formation. Hyperglycemia promotes endothelial matrix remodeling associated with multiple microvascular complications of diabetes, but a role for altered matrix composition in diabetic atherogenesis has not been described. Therefore, we sought to characterize the alterations in matrix composition during diabetic atherogenesis using both in vitro and in vivo model systems.
Methods and Results
Streptozotocin-induced diabetes in atherosclerosis-prone ApoE knockout mice promoted transitional matrix expression (fibronectin, thrombospondin-1) and deposition in intima of the aortic arch as determined by qRT-PCR array and immunohistochemistry. Early plaque formation occurs at discrete vascular sites exposed to disturbed blood flow patterns, whereas regions exposed to laminar flow are protected. Consistent with this pattern, hyperglycemia-induced transitional matrix deposition was restricted to regions of disturbed blood flow. Laminar flow significantly blunted high glucose-induced fibronectin expression (mRNA and protein) and fibronectin fibrillogenesis in endothelial cell culture models, whereas high glucose-induced fibronectin deposition was similar between disturbed flow and static conditions.
Taken together, these data demonstrate that flow patterns and hyperglycemia coordinately regulate subendothelial fibronectin deposition during early atherogenesis.
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