Mechanical stretch-induced fibronectin and transforming growth factor-beta1 production in human mesangial cells is p38 mitogen-activated protein kinase-dependent.

Gruden, Gabriella; Zonca, S; Hayward, A; Thomas, Stephen; Maestrini, Sabrina; Gnudi, Luigi; Viberti, Giancarlo

doi:10.2337/diabetes.49.4.655

Cited by 116 publications

(96 citation statements)

References 19 publications

(17 reference statements)

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“…Phosphorylation of p38 MAPK by hyperglycaemia and/or mechanical stretch promotes mesangial cell production of TGF-β1 and fibronectin [22,23]. TGF-β1 can, in turn, induce the synthesis of collagen and fibronectin by mesangial cells and fibroblasts via a p38-MAPK-dependent pathway [7,8].…”

Section: Introductionmentioning

confidence: 99%

Abnormal p38 mitogen-activated protein kinase signalling in human and experimental diabetic nephropathy

et al. 2004

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Aims/hypothesis. Inflammation and fibrosis are pathological mechanisms that are partially regulated by cell signalling through the p38 mitogen-activated protein kinase (MAPK) pathway. Elements of the diabetic milieu such as high glucose and advanced glycation endproducts induce activation of this pathway in renal cells. Therefore, we examined whether p38 MAPK signalling is associated with the development of human and experimental diabetic nephropathy. Methods. Immunostaining identified phosphorylated (active) p38 MAPK in human biopsies with no abnormality (n=6) and with Type 2 diabetic nephropathy (n=12). Changes in kidney levels of phosphorylated p38 were assessed by immunostaining and western blotting in mice with streptozotocin-induced Type 1 diabetes that had been killed after 0.5, 2, 3, 4 and 8 months, and in Type 2 diabetic db/db mice at 2, 4, 6 and 8 months of age. Results. Phosphorylated p38 was detected in some intrinsic cells in normal human kidney, including podocytes, cortical tubules and occasional interstitial cells. Greater numbers of these phosphorylated p38+ cells were observed in diabetic patients, and phosphorylated p38 was identified in accumulating interstitial macrophages and myofibroblasts. A similar pattern of p38 activation was observed in both mouse models of diabetes. In mice, kidney levels of phosphorylated p38 increased (2-6 fold) following the onset of Type 1 and Type 2 diabetes. In both mouse models, interstitial phosphorylated p38+ cells were associated with hyperglycaemia, increased HbA 1 c levels and albuminuria. Further assessment of streptozotocin-induced diabetic nephropathy showed that interstitial phosphorylated p38+ cells correlated with interstitial fibrosis (myofibroblasts, collagen). Conclusions/interpretation. Increased p38 MAPK signalling is a feature of human and experimental diabetic nephropathy. Time course studies in mouse models suggest that phosphorylation of p38 plays a pathological role, particularly in the development of interstitial fibrosis.

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Section: Introductionmentioning

confidence: 99%

Abnormal p38 mitogen-activated protein kinase signalling in human and experimental diabetic nephropathy

et al. 2004

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“…SB202190 and the rabbit anti-fibronectin antibody were from Calbiochem (Nottingham, UK). The protein kinase C (PKC) peptide inhibitors PKC [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] and SN50 were from Alexis (Nottingham, UK) and the TransAM nuclear factor kappa B (NF-κB) kit was from Active Motif (Rixensart, Belgium). The FITC-conjugated rabbit antimouse antibody, the rabbit anti-fibronectin antibody and the avidin/biotin blocking solution were from DAKOCytomation (Glostrup, Denmark).…”

Section: Methodsmentioning

confidence: 99%

“…After activation of latent TGF-β1 by acidification, total TGF-β1 protein concentration was measured by ELISA (range: 16-1,000 pg/ml; intra-assay CV: 1.6%) using a mouse monoclonal and a rabbit polyclonal anti-human TGF-β1. Fibronectin protein levels were measured using a competitive inhibition ELISA, as previously described (range 0.05-0.5 μg/ml; intra-assay CV 5%) [20]. Collagen IV levels were measured by indirect competitive ELISA (range: 0.02-2.5 μg/ml; intra-assay and inter-assay CV <10%) using collagen type IV-coated plates and a rabbit anticollagen type IV antibody.…”

Section: In Vitro Studymentioning

confidence: 99%

“…Measurements of pericellular polymeric fibronectin Levels of pericellular polymeric fibronectin were determined in deoxycholate-insoluble and sodium dodecyl sulfate (SDS)-soluble protein extracts as previously described [20,21].…”

Section: In Vitro Studymentioning

confidence: 99%

“…Inhibition experiments on basal protein production were carried out simultaneously. RS102895 (6 μmol/l), anti-TGF-β1 neutralising antibody (2 μg/ml), SN50 (18 μmol/l), SB202190 (1 μmol/l) and PKC [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] (4 μmol/l) were used to block CCR2, TGF-β1, NF-κB, p38 mitogen-activated protein (MAP) kinase and PKC, respectively. The specificity and selectivity of the inhibitors used has been previously demonstrated [22][23][24][25].…”

Section: In Vitro Studymentioning

confidence: 99%

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Monocyte chemoattractant protein-1 has prosclerotic effects both in a mouse model of experimental diabetes and in vitro in human mesangial cells

et al. 2007

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Aims/hypothesis Diabetic nephropathy is characterised by mesangial extracellular matrix accumulation. Monocyte chemoattractant protein-1 (MCP-1), a chemokine promoting monocyte infiltration, is upregulated in the diabetic glomerulus. We performed in vitro and in vivo studies to examine whether MCP-1 may have prosclerotic actions in the setting of diabetes, presumably via its receptor, chemokine (C-C motif) receptor 2 (CCR2), which has been described in mesangial cells. Methods Human mesangial cells were exposed to recombinant human (rh)-MCP-1 (100 ng/ml) for 12, 24 and 48 h and to rh-MCP-1 (10, 100 and 200 ng/ml) for 24 h. Fibronectin, collagen IV and transforming growth factor, beta 1 (TGF-β1) protein levels were measured by ELISA and pericellular polymeric fibronectin levels by western blotting. The intracellular mechanisms were investigated using specific inhibitors for CCR2, nuclear factor kappa B (NF-κB), p38 mitogen-activated protein kinase and protein kinase C, and an anti-TGF-β1 blocking antibody. In both non-diabetic and streptozotocin-induced diabetic mice that were deficient or not in MCP-1, glomerular fibronectin accumulation was examined by immunohistochemistry, while cortical Tgf-β1 (also known as Tgfb1) and fibronectin mRNA and protein levels were examined by real-time PCR and western blotting. Results In mesangial cells, MCP-1 binding to CCR2 induced a 2.5-fold increase in fibronectin protein levels at 24 h followed by a rise in pericellular fibronectin, whereas no changes were seen in collagen IV production. MCP-1-induced fibronectin production was TGF-β1-and NF-κB-dependent. In diabetic mice, loss of MCP-1 diminished glomerular fibronectin protein production and both renal cortical Tgf-β1 and fibronectin mRNA and protein levels. Conclusions/interpretation Our in vitro and in vivo findings indicate a role for the MCP-1/CCR2 system in fibronectin deposition in the diabetic glomerulus, providing a new therapeutic target for diabetic nephropathy.

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The Microcirculation in Diabetes Mellitus

Tooke

2003

International Textbook of Diabetes Mellitus

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Examination of human microvascular function in the two major forms of diabetes has revealed common abnormalities yet important differences in microvascular behavior. Early microvascular hypertension related to the degree of hyperglycemia appears to be fundamental to the expression of microangiopathy in type 1 diabetes millitus (T1DM), and although plausible biochemical explanations exist for this phenomenon, they remain to be verified in human diabetes. In type 2 diabetes millitus (T2DM) the interplay between preceding insulin resistance, hypertension, and vascular smooth muscle function modifies and confuses the pathophysiological findings, particularly in view of the fact that the emergence of hyperglycemia is difficult to date in this form of the disease. Unraveling of this puzzle may explain the subtle differences in the expression of microangiopathy in T1DM and T2DM, whereas primary manipulation of the hemodynamic and permeability changes may offer real therapeutic potential in the future.

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Mechanical stretch-induced fibronectin and transforming growth factor-beta1 production in human mesangial cells is p38 mitogen-activated protein kinase-dependent.

Cited by 116 publications

References 19 publications

Abnormal p38 mitogen-activated protein kinase signalling in human and experimental diabetic nephropathy

Abnormal p38 mitogen-activated protein kinase signalling in human and experimental diabetic nephropathy

Monocyte chemoattractant protein-1 has prosclerotic effects both in a mouse model of experimental diabetes and in vitro in human mesangial cells

The Microcirculation in Diabetes Mellitus

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