Decreased Expression of Pigment Epithelium-Derived Factor Is Involved in the Pathogenesis of Diabetic Nephropathy

Wang, Joshua J.; Zhang, Sarah X.; Lu, Kangmo; Chen, Ying; Mott, Robert; Sato, Sanai; Xing, Jian

doi:10.2337/diabetes.54.1.243

Cited by 80 publications

(94 citation statements)

References 38 publications

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“…These differences likely reflect tissue-specific PEDF gene expression, whereby the liver had the highest expression levels, whereas those in the pancreas were low. 44 Other studies 7,45,46 indicate significant PEDF production by organs, such as the kidney and adipose tissue, and suggest that an increased distribution may occur under inflammatory conditions, such as obesity. Given PEDF's role in ameliorating tissue fibrosis, the contribution of other organs may be reflected in circulating systemic levels.…”

Section: Discussionmentioning

confidence: 99%

“…10 The antifibrogenic properties of PEDF have also been demonstrated in other organs, including the kidney, heart, and eye. 7,8,18,19 PEDF delivery ameliorated kidney fibrosis and proteinuria by suppressing transforming growth factor (TGF)-␤1 expression in diabetic rats. 8 Similarly, in a model of acute myocardial infarction, PEDF infusion reduced cardiac fibrosis through down-regulation of TGF-␤1 and fibrillar collagen expression, thereby improving left ventricular ejection.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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“…PEDF, which has anti-oxidant, anti-inflammatory and anti-angiogenic effects, has been closely associated with diabetic vascular disease, particularly retinopathy [13,14]. Plasma PEDF levels are increased in metabolic syndrome [18] and in type 1 and type 2 diabetes in the presence of complications [19,20].…”

Section: Discussionmentioning

confidence: 99%

“…A recent study in non-diabetic women indicated that rising serum endoglin and sFlt1/PlGF ratio herald the onset of pre-eclampsia [7]. Pigment epithelium-derived factor (PEDF), a novel anti-angiogenic protein, is also altered in diabetes and its increased serum levels are associated with diabetic vascular complications [13,14]. Although it is unclear whether PEDF is released from placental tissues in pre-eclampsia, PEDF could be implicated as a maternal risk factor in the pathogenesis of pre-eclampsia.…”

Section: Introductionmentioning

confidence: 99%

Anti-angiogenic factors and pre-eclampsia in type 1 diabetic women

Jenkins

Nankervis

et al. 2008

Diabetologia

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Aims/hypothesis Elevated anti-angiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt1), a soluble form of vascular endothelial growth factor receptor, and endoglin, a co-receptor for TGFβ1, confer high risk of pre-eclampsia in healthy pregnant women. In this multicentre prospective study, we determined levels of these and related factors in pregnant women with type 1 diabetes, a condition associated with a fourfold increase in pre-eclampsia. Methods Maternal serum sFlt1, endoglin, placental growth factor (PlGF) and pigment epithelial-derived factor were measured in 151 type 1 diabetic and 24 healthy non-diabetic women at each trimester and at term. Diabetologia (2009) Results Approximately 22% of the diabetic women developed pre-eclampsia, primarily after their third trimester visit. In women with pre-eclampsia (diabetic pre-eclampsia, n=26) vs those without hypertensive complications (diabetic normotensive, n=95), significant changes in angiogenic factors were observed, predominantly in the early third trimester and prior to clinical manifestation of pre-eclampsia. Serum sFlt1 levels were increased approximately twofold in type 1 diabetic pre-eclampsia vs type 1 diabetic normotensive women at the third trimester visit (p<0.05) and the normal rise of PlGF during pregnancy was blunted (p<0.05). Among type 1 diabetic women, third trimester sFlt1 and PlGF were inversely related (r 2 =42%, p<0.0001). Endoglin levels were increased significantly in the diabetic group as a whole vs the non-diabetic group (p<0.0001). Conclusions/interpretation Higher sFlt1 levels, a blunted PlGF rise and an elevated sFlt1/PlGF ratio are predictive of pre-eclampsia in pregnant women with type 1 diabetes. Elevated endoglin levels in women with type 1 diabetes may confer a predisposition to pre-eclampsia and may contribute to the high incidence of pre-eclampsia in this patient group.

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“…Primary human glomerular mesangial cell (HMC) culture was described previously (31). Cells of passages 6 to 10 were used in the experiments.…”

Section: Cell Culturementioning

confidence: 99%

Therapeutic Potential of Angiostatin in Diabetic Nephropathy

Zhang¹,

Wang²,

Lu³

et al. 2006

Journal of the American Society of Nephrology

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Angiostatin is a proteolytic fragment of plasminogen and a potent angiogenic inhibitor. Previous studies have shown that angiostatin inhibits retinal neovascularization and reduces retinal vascular permeability in diabetic retinopathy. Here, it is reported for the first time that angiostatin is also implicated in diabetic nephropathy (DN). Angiostatin levels are dramatically decreased in the kidney of streptozotocin-induced diabetic rats. Consistently, diabetic kidneys also showed decreased expression and proteolytic activities of matrix metalloproteinase-2, an enzyme that releases angiostatin from plasminogen. Adenovirus-mediated delivery of angiostatin significantly alleviated albuminuria and attenuated the glomerular hypertrophy in diabetic rats. Moreover, angiostatin treatment downregulated the expression of vascular endothelial growth factor and TGF-␤1, two major pathogenic factors of DN, in diabetic kidneys. In cultured human mesangial cells, angiostatin blocked the overexpression of vascular endothelial growth factor and TGF-␤1 that were induced by high glucose while increasing the levels of pigment epithelium-derived factor, an endogenous inhibitor of DN. Moreover, angiostatin effectively inhibited the high-glucose-and TGF-␤1-induced overproduction of proinflammatory factors and extracellular matrix proteins via blockade of the Smad signaling pathway. These findings suggest that the decrease of angiostatin levels in diabetic kidney may contribute to the pathologic changes such as inflammation and fibrosis in DN. Therefore, angiostatin has therapeutic potential in DN as a result of its anti-inflammatory and antifibrosis activities.

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Decreased Expression of Pigment Epithelium-Derived Factor Is Involved in the Pathogenesis of Diabetic Nephropathy

Cited by 80 publications

References 38 publications

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

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

Anti-angiogenic factors and pre-eclampsia in type 1 diabetic women

Therapeutic Potential of Angiostatin in Diabetic Nephropathy

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