A Thrombospondin-1 Antagonist of Transforming Growth Factor-β Activation Blocks Cardiomyopathy in Rats with Diabetes and Elevated Angiotensin II

Belmadani, Souâd; Bernal, Juan; Wei, Chih‐Chang; Pallero, Manuel A.; Dell’Italia, Louis J.; Murphy-Ullrich, Joanne E.; Berecek, Kathleen H.

doi:10.2353/ajpath.2007.070056

Cited by 103 publications

(90 citation statements)

References 77 publications

(86 reference statements)

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“…Moreover, LSKL treatment did not have any demonstrable effects on tissue homeostasis in wild-type C57BL/6J (data not shown), similar to our observations in normal rats receiving long-term LSKL peptide treatment. 39 In conclusion, these studies establish that blockade of TSP1-mediated TGF-␤ activation is an effective therapeutic target for treatment of the renal complications of diabetes. These studies suggest that blockade of TSP1-mediated TGF-␤ activation is a selective approach to controlling excessive TGF-␤ levels in diabetes and lacks the adverse effects associated with global inhibition of TGF-␤ signaling.…”

Section: Discussionmentioning

confidence: 68%

“…7,30,35,36,38,39,53,54 In the present studies, we addressed whether selective targeting of only TGF-␤ activated by TSP1 would be an effective approach to reduce renal dysfunction in a mouse model of type 1 diabetes. These studies showed that i.p.…”

Section: Discussionmentioning

confidence: 99%

“…38 Moreover, antagonism of TSP1-dependent TGF-␤ activation by treatment with a peptide antagonist of TSP1-dependent TGF-␤ activation, LSKL, reversed myocardial fibrosis and improved left ventricular function by reducing TGF-␤ activity in diabetic rats. 39 Together, these results suggest that the TSP1-TGF-␤ axis is a key regulator of fibrotic diabetic complications.…”

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confidence: 84%

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Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy

Miao

Schoeb

et al. 2011

The American Journal of Pathology

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Transforming growth factor-␤ (TGF-␤) is key in the pathogenesis of diabetic nephropathy. Thrombospondin 1 (TSP1) expression is increased in diabetes, and TSP1 regulates latent TGF-␤ activation in vitro and in diabetic animal models. Herein, we investigate the effect of blockade of TSP1-dependent TGF-␤ activation on progression of renal disease in a mouse model of type 1 diabetes (C57BL/6J-Ins2 Akita ) as a targeted treatment for diabetic nephropathy. Akita and control C57BL/6 mice who underwent uninephrectomy received 15 weeks of thrice-weekly i.p. treatment with 3 or 30 mg/kg LSKL peptide, control SLLK peptide, or saline. The effects of systemic LSKL peptide on dermal wound healing was assessed in type 2 diabetic mice (db/db). Proteinuria (urinary albumin level and albumin/creatinine ratio) was significantly improved in Akita mice treated with 30 mg/kg LSKL peptide. LSKL treatment reduced urinary TGF-␤ activity and renal phospho-Smad2/3 levels and improved markers of tubulointerstitial injury (fibronectin) and podocytes (nephrin). However, LSKL did not alter glomerulosclerosis or glomerular structure. LSKL did not increase tumor incidence or inflammation or impair diabetic wound healing. These data suggest that selective targeting of excessive TGF-␤ activity through blockade of TSP1-dependent TGF-␤ activation represents a therapeutic strategy for treating diabetic nephropathy that preserves the homeostatic functions of TGF-␤.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 84%

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Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy

Miao

Schoeb

et al. 2011

The American Journal of Pathology

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“…[22][23][24] TSP-1 blockade has been shown to reduce TGF-␤1 signaling and tissue fibrosis. [25][26][27][28] TSP-1 expression also markedly increased after experimental acute pancreatitis. 22 Thus, it would be expected that PEDF and TSP-1 would be reciprocally regulated if PEDF functions to inhibit fibrosis in the pancreas.…”

mentioning

confidence: 90%

Pigment Epithelium-Derived Factor Regulates Early Pancreatic Fibrotic Responses and Suppresses the Profibrotic Cytokine Thrombospondin-1

Schmitz

Protiva

Gattu

et al. 2011

The American Journal of Pathology

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Pigment epithelium-derived factor (PEDF) is important for maintaining the normal extracellular matrix. We hypothesized that the initiation of pancreatic fibrosis is dependent on the loss of PEDF. Pancreatic PEDF expression was assessed in wild-type mice fed either a control or ethanol diet using an intragastric feeding model. Pancreatitis responses were elicited with either a single episode or a repetitive ceruleininduced (50 g/kg, 6 hourly i.p. injections) protocol in wild-type and PEDF-null mice. Quantitative realtime PCR and immunoblotting were performed to assess fibrogenic responses. In wild-type animals, PEDF expression increased with pancreatitis and was more pronounced in mice fed ethanol. Compared with wild-type mice, ␣-smooth muscle actin staining and expression levels of fibrogenic markers (eg, transforming growth factor-␤1, platelet-derived growth factor, collagen I, and thrombospondin-1) were higher in PEDF-null mice at baseline. Sirius red staining revealed more fibrosis in PEDF-null versus wildtype pancreas 1 week after pancreatitis. Differences in tissue fibrosis resolved with longer recovery periods. PEDF overexpression suppressed thrombospondin-1 levels in vitro. Ethanol feeding and experimental pancreatitis increased PEDF expression in wildtype mice. PEDF-null mice, however, demonstrated enhanced early fibrotic responses compared with wildtype mice with pancreatitis. These findings indicate that PEDF acts as a compensatory antifibrotic cytokine in

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“…TSP-1 promotes the events associated with diabetic nephropathy: mesangial cell proliferation and increased matrix production by mesangial cells (21)(22)(23)(24). A peptide blocking the activation of transforming growth factor-␤ activation by TSP-1 prevented progression of cardiac fibrosis and improved cardiac function in a rat model, implicating TSP-1 in development of diabetic cardiomyopathy (25). Recently, we reported increased levels of TSP-1 in macrovessels of diabetic Zucker rats (26).…”

mentioning

confidence: 98%

Cell Type-specific Post-transcriptional Regulation of Production of the Potent Antiangiogenic and Proatherogenic Protein Thrombospondin-1 by High Glucose

Bhattacharyya

Marinic

Krukovets

et al. 2008

Journal of Biological Chemistry

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Hyperglycemia is an independent risk factor for development of vascular diabetic complications. Vascular dysfunction in diabetics manifests in a tissue-specific manner; macrovasculature is affected by atherosclerotic lesions, and microvascular complications are described as "aberrant angiogenesis": in the same patient angiogenesis is increased in some tissues (e.g. retinal neovascularization) and decreased in others (e.g. in skin). Molecular cell-and tissue-specific mechanisms regulating the response of vasculature to hyperglycemia remain unclear. Thrombospondin-1 (TSP-1), a potent antiangiogenic and proatherogenic protein, has been implicated in the development of several vascular diabetic complications (atherosclerosis, nephropathy, and cardiomyopathy). This study examines cell type-specific regulation of production of thrombospondin-1 by high glucose. We previously reported the increased expression of TSP-1 in the large arteries of diabetic animals. mRNA and protein levels were up-regulated in response to high glucose. Unlike in macrovascular cells, TSP-1 protein levels are dramatically decreased in response to high glucose in microvascular endothelial cells and retinal pigment epithelial cells (RPE). This downregulation is post-transcriptional; mRNA levels are increased. In situ mRNA hybridization and immunohistochemistry revealed that the level of mRNA is up-regulated in RPE of diabetic rats, whereas the protein level is decreased. This cell type-specific posttranscriptional suppression of TSP-1 production in response to high glucose in microvascular endothelial cells and RPE is controlled by untranslated regions of TSP-1 mRNA that regulate coupling of TSP-1 mRNA to polysomes and its translation. The cellspecific regulation of TSP-1 suggests a potential mechanism for the aberrant angiogenesis in diabetics and TSP-1 involvement in development of various vascular diabetic complications.Despite the significant advances in the therapeutic methods to control blood glucose and insulin levels in diabetic patients, the precise regulation of these levels remains a problem. Vascular diabetic complications remain most prevalent and dangerous and account for the greatest numbers of deaths and hospitalizations in diabetic patients. The molecular basis for the vascular complications of diabetes is not well understood. Recent reports indicate that both microvascular and macrovascular complications of diabetes correlate directly with glucose levels in both patients and animal models (1-5). Some of these reports revealed the pathogenic role of impaired glucose tolerance and post-prandial hyperglycemia even in the absence of diabetes, e.g. (6). In vascular cells, glucose regulates expression of many genes that have been linked to the development of atherosclerosis or abnormal angiogenesis (reviewed in Ref. 7). One of them is thrombospondin-1 (TSP-1), 3 a cell matrix protein implicated in both atherogenesis (8 -12) and angiogenesis (13)(14)(15)(16)(17)(18)(19). Several lines of evidence indicate that TSP-1 may represent a lin...

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A Thrombospondin-1 Antagonist of Transforming Growth Factor-β Activation Blocks Cardiomyopathy in Rats with Diabetes and Elevated Angiotensin II

Cited by 103 publications

References 77 publications

Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy

Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy

Pigment Epithelium-Derived Factor Regulates Early Pancreatic Fibrotic Responses and Suppresses the Profibrotic Cytokine Thrombospondin-1

Cell Type-specific Post-transcriptional Regulation of Production of the Potent Antiangiogenic and Proatherogenic Protein Thrombospondin-1 by High Glucose

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