Heparan sulfate proteoglycan synthesis and its expression are decreased in the retina of diabetic rats

Bollineni, Jaya; Alluru, Indira; Reddi, Alluru S.

doi:10.1076/ceyr.16.2.127.5089

Cited by 39 publications

(20 citation statements)

References 25 publications

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“…High glucose levels upregulate cell-associated proteoglycans in retinal pericytes 58 and promote the secretion of HS chains by endothelial cells, 59 and VEGF increases the retinal expression of the HS side chains of HSPGs. 60 Perlecan binds FGFs, 61,62 and the intraretinal stores of immunoreactive bFGF and HSPG increase in patients with DR. 63 Of note, abnormal HSPG expression and structure can contribute to vascular leakage and to the release of pro-angiogenic factors in DR, 64 whereas bFGF, αvβ5 integrin, and HGF can signal to promote angiogenesis in DR. 65 However, contrary to what is expected from our findings using rats after 6 weeks of STZ, the mRNA levels of perlecan, the [ 35 S] sulfate incorporation into HSPG, 66 and the immunolocalization of HSPG 67 decrease in the retina of diabetic rats at 5 and 11 months after STZ treatment, respectively. These findings suggest that the synthesis of HSPG may change as diabetes progresses and emphasize the need to examine the long-term differential efficacy of AAV2 vectors.…”

Section: Aav2 Vectors Reverse Diabetic Retinal Alterations N Díaz-lezcontrasting

confidence: 55%

Diabetes enhances the efficacy of AAV2 vectors in the retina: therapeutic effect of AAV2 encoding vasoinhibin and soluble VEGF receptor 1

Díaz‐Lezama

Adán‐Castro

et al. 2016

Laboratory Investigation

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Adeno-associated virus (AAV) vector-mediated delivery of inhibitors of blood-retinal barrier breakdown (BRBB) offers promise for the treatment of diabetic macular edema. Here, we demonstrated a reversal of blood-retinal barrier pathology mediated by AAV type 2 (AAV2) vectors encoding vasoinhibin or soluble VEGF receptor 1 (sFlt-1) when administered intravitreally to diabetic rats. Efficacy and safety of the AAV2 vasoinhibin vector were tested by monitoring its effect on diabetes-induced changes in the retinal vascular bed and thickness, and in the electroretinogram (ERG). Also, the transduction of AAV2 vectors and expression of AAV2 receptors and co-receptors were compared between the diabetic and the non-diabetic rat retinas. AAV2 vasoinhibin or AAV2 sFlt-1 vectors were injected intravitreally before or after enhanced BRBB due to diabetes induced by streptozotocin. The BRBB was examined by the Evans blue method, the vascular bed by fluorescein angiography, expression of the AAV2 EGFP reporter vector by confocal microscopy, and the AAV2 genome, expression of transgenes, receptors, and co-receptors by quantitative PCR. AAV2 vasoinhibin and sFlt-1 vectors inhibited the diabetes-mediated increase in BRBB when injected after, but not before, diabetes was induced. The AAV2 vasoinhibin vector decreased retinal microvascular abnormalities and the diabetes-induced reduction of the B-wave of the ERG, but it had no effect in non-diabetic controls. Also, retinal thickness was not altered by diabetes or by the AAV2 vasoinhibin vector. The AAV2 genome, vasoinhibin and sFlt-1 transgenes, and EGFP levels were higher in the retinas from diabetic rats and were associated with an elevated expression of AAV2 receptors (syndecan, glypican, and perlecan) and co-receptors (fibroblast growth factor receptor 1, αvβ5 integrin, and hepatocyte growth factor receptor). We conclude that retinal transduction and efficacy of AAV2 vectors are enhanced in diabetes, possibly due to their elevated cell entry. AAV2 vectors encoding vasoinhibin and sFlt-1 may be desirable gene therapeutics to target diabetic retinopathy and macular edema.

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Section: Aav2 Vectors Reverse Diabetic Retinal Alterations N Díaz-lezcontrasting

confidence: 55%

Diabetes enhances the efficacy of AAV2 vectors in the retina: therapeutic effect of AAV2 encoding vasoinhibin and soluble VEGF receptor 1

Díaz‐Lezama

Adán‐Castro

et al. 2016

Laboratory Investigation

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“…It has been demonstrated that perlecan core protein is downregulated in the liver of diabetic patients (24). In the retinal basement membrane of diabetic patients, a diminished or unaltered perlecan expression has been reported (25,26). Thus far, no report exists about the expression of perlecan in the kidney of humans or animals with diabetes.…”

Section: Discussionmentioning

confidence: 94%

Diminished Loss of Proteoglycans and Lack of Albuminuria in Protein Kinase C-α—Deficient Diabetic Mice

et al. 2004

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Activation of protein kinase C (PKC) isoforms has been implicated in the pathogenesis of diabetic nephropathy. We showed earlier that PKC-␣ is activated in the kidneys of hyperglycemic animals. We now used PKC-␣ ؊/؊ mice to test the hypothesis that this PKC isoform mediates streptozotocin-induced diabetic nephropathy. We observed that renal and glomerular hypertrophy was similar in diabetic wild-type and PKC-␣ ؊/؊ mice. However, the development of albuminuria was almost absent in the diabetic PKC-␣ ؊/؊ mice. The hyperglycemia-induced downregulation of the negatively charged basement membrane heparan sulfate proteoglycan perlecan was completely prevented in the PKC-␣ ؊/؊ mice, compared with controls. We then asked whether transforming growth factor-␤1 (TGF-␤ 1 ) and/or vascular endothelial growth factor (VEGF) is implicated in the PKC-␣-mediated changes in the basement membrane. The hyperglycemia-induced expression of VEGF165 and its receptor VEGF receptor II (flk-1) was ameliorated in PKC-␣ ؊/؊ mice, whereas expression of TGF-␤ 1 was not affected by the lack of PKC-␣. Our findings indicate that two important features of diabetic nephropathy-glomerular hypertrophy and albuminuria-are differentially regulated. The glucose-induced albuminuria seems to be mediated by PKC-␣ via downregulation of proteoglycans in the basement membrane and regulation of VEGF expression. Therefore, PKC-␣ is a possible therapeutic target for the prevention of diabetic albuminuria.

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“…Decreased HSPG in DM has been studied predominantly in the context of diabetic nephropathy, although it has been observed in a variety of tissues (82)(83)(84). Decreased expression of perlecan, specifically, has been described in a variety of renal models (85,86).…”

Section: Figurementioning

confidence: 99%

Delayed catabolism of apoB-48 lipoproteins due to decreased heparan sulfate proteoglycan production in diabetic mice

Ebara¹,

Conde²,

Kako³

et al. 2000

J. Clin. Invest.

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We used wild-type (WT) mice and mice engineered to express either apoB-100 only (B100 mice) or apoB-48 only (B48 mice) to examine the effects of streptozotocin-induced diabetes (DM) on apoB-100-and apoB-48-containing lipoproteins. Plasma lipids increased with DM in WT mice, and fat tolerance was markedly impaired. Lipoprotein profiles showed increased levels and cholesterol enrichment of VLDL in diabetic B48 mice but not in B100 mice. C apolipoproteins, in particular apoC-I in VLDL, were increased. To investigate the basis of the increase in apoB-48 lipoproteins in streptozotocin-treated animals, we characterized several parameters of lipoprotein metabolism. Triglyceride and apoB production rates were normal, as were plasma lipase activity, VLDL glycosaminoglycan binding, and VLDL lipolysis. However, β-VLDL clearance decreased due to decreased trapping by the liver. Whereas LRP activity was normal, livers from treated mice incorporated significantly less sulfate into heparan sulfate proteoglycans (HSPG) than did controls. Hepatoma (HepG2) cells and endothelial cells cultured in high glucose also showed decreased sulfate and glucosamine incorporation into HSPG. Western blots of livers from diabetic mice showed a decrease in the HSPG core protein, perlecan. Delayed clearance of postprandial apoB-48-containing lipoproteins in DM appears to be due to decreased hepatic perlecan HSPG.

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Heparan sulfate proteoglycan synthesis and its expression are decreased in the retina of diabetic rats

Abstract: The decrease in HSPG synthesis may account for the reported decrease in retinal basement membrane anionic sites and increased capillary permeability that occurs in diabetes.

Cited by 39 publications

References 25 publications

Diabetes enhances the efficacy of AAV2 vectors in the retina: therapeutic effect of AAV2 encoding vasoinhibin and soluble VEGF receptor 1

Diabetes enhances the efficacy of AAV2 vectors in the retina: therapeutic effect of AAV2 encoding vasoinhibin and soluble VEGF receptor 1

Diminished Loss of Proteoglycans and Lack of Albuminuria in Protein Kinase C-α—Deficient Diabetic Mice

Delayed catabolism of apoB-48 lipoproteins due to decreased heparan sulfate proteoglycan production in diabetic mice

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