Inhibition of the JAK/STAT Signaling Pathway Prevents the High Glucose-Induced Increase in TGF-β and Fibronectin Synthesis in Mesangial Cells

Wang, Xiaodan; Shaw, Seán; Amiri, Farhad; Eaton, Douglas C.; Marrero, Mario B.

doi:10.2337/diabetes.51.12.3505

Cited by 164 publications

(157 citation statements)

References 18 publications

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“…Recruitment of these cytokines leads to overexpression of their receptors and activation of their corre- sponding signaling pathways, such as phosphorylation of IRS-1 and Erk1/2 for IGF-1 and of Smad for TGF-␤1. These phenomena are paralleled by the progression of glomerulosclerosis strongly suggesting a link of causality that is sustained by the beneficial effects of their blockades (20,60,69). Reducing hyperglycemia with insulin not only reverses both receptor overexpression and activation of these signaling pathways, but it also delays formation of renal lesions.…”

Section: Discussionmentioning

confidence: 92%

ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats

Allard¹,

Buléon²,

Cellier³

et al. 2007

American Journal of Physiology-Renal Physiology

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Tack I, Girolami J-P. ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats. Am J Physiol Renal Physiol 293: F1083-F1092, 2007. First published June 27, 2007; doi:10.1152/ajprenal.00401.2006 is associated with increased oxidative stress, overexpression and activation of growth factor receptors, including those for transforming growth factor-␤1 (TGF-␤-RII), platelet-derived growth factor (PDGF-R), and insulin-like growth factor (IGF1-R). These pathways are believed to represent pathophysiological determinants of DN. Beyond perfect glycemic control, angiotensin-converting enzyme inhibitors (ACEI) are the most efficient treatment to delay glomerulosclerosis. Since their mechanisms of action remain uncertain, we investigated the effect of ACEI on the glomerular expression of these growth factor pathways in a model of streptozotocin-induced diabetes in rats. The early phase of diabetes was found to be associated with an increase in glomerular expression of IGF1-R, PDGF-R, and TGF-␤-RII and activation of IRS1, Erk 1/2, and Smad 2/3. These changes were significantly reduced by ACEI treatment. Furthermore, ACEI stimulated glutathione peroxidase activity, suggesting a protective role against oxidative stress. ACEI decreased ANG II production but also increased bradykinin bioavailability by reducing its degradation. Thus the involvement of the bradykinin pathway was investigated using coadministration of HOE-140, a highly specific nonpeptidic B2-kinin receptor antagonist. Almost all the previously described effects of ACEI were abolished by HOE-140, as was the increase in glutathione peroxidase activity. Moreover, the well-established ability of ACEI to reduce albuminuria was also prevented by HOE-140. Taken together, these data demonstrate that, in the early phase of diabetes, ACEI reverse glomerular overexpression and activation of some critical growth factor pathways and increase protection against oxidative stress and that these effects involve B2-kinin receptor activation.angiotensin-converting enzyme inhibitor; oxidative stress; glutathione peroxidase activity; diabetes DIABETIC NEPHROPATHY (DN) causes the majority of end-stage renal diseases throughout the world (54). It was initially believed that elevated blood glucose was the major cause of renal damage in both type 1 and 2 diabetes. However, several clinical studies have demonstrated that strict glycemic control is not sufficient to prevent the progression of renal dysfunction and the development of glomerular lesions. The mechanisms underlying the progression of diabetic kidney disease are intricate and still not completely understood. Among the many pathophysiological mechanisms possible, several growth factors and cytokines have been put forward to account for the onset of DN. This is particularly the case for the paracrine expression of insulin-like growth factor-1 (IGF-1), transforming growth factor-␤ (TGF-␤) (20), and platelet-derived growth factor (PDG...

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Section: Discussionmentioning

confidence: 92%

ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats

Allard¹,

Buléon²,

Cellier³

et al. 2007

American Journal of Physiology-Renal Physiology

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“…A ativação de JAK2 é essencial para a indução da produção de colágeno tipo IV e proliferação induzida tanto pela alta concentração de glicose como também pela AII. Além disso, estudos desse mesmo grupo demonstraram que a ativação de JAK2 e STAT1 é um processo necessário para a indução da produção de TGF-β1 e fibronectina estimulada pela alta concentração de glicose nas células mesangiais (98).…”

Section: Eventos Moleculares Da Lesão Renal Associados Ao Sistema Renunclassified

Bases moleculares da glomerulopatia diabética

Lagranha¹,

Fiorino²,

Casarini

et al. 2007

Arq Bras Endocrinol Metab

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RESUMOO principal determinante da nefropatia diabética é a hiperglicemia, mas hipertensão e fatores genéticos também estão envolvidos. O glomérulo é o foco de lesão, onde proliferação celular mesangial e produção excessiva de matriz extracelular decorrem do aumento da glicose intracelular, por excesso de glicose extracelular e hiperexpressão de GLUT1. Seguem-se aumento do fluxo pela via dos polióis, estresse oxidativo intracelular, produção intracelular aumentada de produtos avançados da glicação não enzimática (AGEs), ativação da via da PKC, aumento da atividade da via das hexosaminas e ativação de TGF-β1. Altas concentrações de glicose também aumentam angiotensina II (AII) nas células mesangiais por aumento intracelular da atividade da renina (ações intrácrinas, mediando efeitos proliferativos e inflamatórios diretamente). Portanto, glicose e AII exercem efeitos proliferativos celulares e de matriz extracelular nas células mesangiais, utilizando vias de transdução de sinais semelhantes, que levam a aumento de TGF-β1. Nesse estudo são revisadas as vias que sinalizam os efeitos da glicose e AII nas células mesangiais em causar os eventos-chaves relacionados à gênese da glomerulopatia diabética. As alterações das vias de sinalização implicadas na glomerulopatia, aqui revisadas, suportam dados de estudos observacionais/ensaios clínicos, onde controle metabólico e anti-hipertensivo, especificamente com inibidores do sistema renina-angiotensina, têm-se mostrado importantes -e aditivos -na prevenção do início e progressão da nefropatia. Novas estratégias terapêuticas dirigidas aos eventos intracelulares descritos deverão futuramente promover benefício adicional. ABSTRACT Molecular Bases of Diabetic Nephropathy.The determinant of the diabetic nephropathy is hyperglycemia, but hypertension and other genetic factors are also involved. Glomerulus is the focus of the injury, where mesangial cell proliferation and extracellular matrix occur because of the increase of the intra-and extracellular glucose concentration and overexpression of GLUT1. Sequentially, there are increases in the flow by the poliol pathway, oxidative stress, increased intracellular production of advanced glycation end products (AGEs), activation of the PKC pathway, increase of the activity of the hexosamine pathway, and activation of TGF-β1. High glucose concentrations also increase angiotensin II (AII) levels. Therefore, glucose and AII exert similar effects in inducing extracellular matrix formation in the mesangial cells, using similar transductional signal, which increases TGF-β1 levels. In this review we focus in the effect of glucose and AII in the mesangial cells in causing the events related to the genesis of diabetic nephropathy. The alterations in the signal pathways discussed in this review give support to the observational studies and clinical assays, where metabolic and antihypertensive controls obtained with angiotensin-converting inhibitors have shown important and additive effect in the prevention of the beginning and progression of d...

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“…However, TGF-β was not found to represent a genetic susceptibility locus for diabetic nephropathy in type 1 diabetes: genetic variations of the TGF-β1 locus were similar in patients with type 1 diabetes regardless of whether they had nephropathy or not [30]. Signalling pathways involved in the modulation of matrix protein expression in diabetic nephropathy include the activation of protein kinase C (PKC) [31,32], as well as FAK, ERK, MAPK, JNK/SAPK, and Jak/STAT [33][34][35][36]. PKC activation was observed to accompany glucose-induced overexpression of intercellular adhesion molecule-1 (ICAM-1), and involved also the activation of transcription factor NF-κB [37].…”

Section: Glomerular Basement Membrane (Gbm)mentioning

confidence: 99%

Microvascular basement membranes in diabetes mellitus

Tsilibary

2003

The Journal of Pathology

242

156

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The alterations in the microvascular system of diabetes mellitus patients are responsible for the most devastating complications of this widespread disease. In the kidney, the microangiopathy leads to thickening of the glomerular capillary basement membrane but also to the expansion of the mesangial matrix and thickening of the tubular basement membrane. Several mechanisms are implicated in the pathogenesis of diabetic renal microangiopathy. These include increased synthesis of type IV collagen following hyperglycaemia-induced alteration of the pattern of podocyte-integrin expression, decreased expression of matrix metalloproteinases (MMP-2 and 3), and increased expression of tissue inhibitor of metalloproteinase (TIMP). An altered morphology of podocytes accompanies these basement membrane alterations. Other factors which may contribute to renal matrix accumulation include vascular endothelial growth factor (VEGF), since treatment with anti-VEGF antibodies attenuates glomerular basement membrane thickening, platelet-derived growth factor (PDGF) (B chain) and its receptor, which appear to be highly expressed in mesangial and visceral epithelial cells and might play a role in the development of diabetic nephropathy. Also oxygen radicals/oxidative stress may play a role in matrix accumulation in diabetic nephropathy as aminoguanidine, an inhibitor of the formation of advanced glycation endproducts but with antioxidant properties, attenuates diabetic nephropathy. Retinal diabetic microangiopathy follows much the same principles, be it that microvascular proliferation is a distinctive element in the retina. Nephropathy and retinopathy occur frequently but not always together, indicating that in their multifactorial pathogenesis much remains to be clarified.

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Inhibition of the JAK/STAT Signaling Pathway Prevents the High Glucose-Induced Increase in TGF-β and Fibronectin Synthesis in Mesangial Cells

Cited by 164 publications

References 18 publications

ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats

ACE inhibitor reduces growth factor receptor expression and signaling but also albuminuria through B2-kinin glomerular receptor activation in diabetic rats

Bases moleculares da glomerulopatia diabética

Microvascular basement membranes in diabetes mellitus

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