Tyrosine kinase dependent expression of TGF-β induced by stretch in mesangial cells

Hirakata, Masao; Kaname, Shinya; Chung, Ung‐il; Joki, Nobuhiko; Hori, Yoshiaki; Noda, Masakuni; Takuwa, Yoh; Okazaki, Taro; Fujita, Toshiro; Katoh, Tetsuo; Kurokawa, Kiyoshi

doi:10.1038/ki.1997.144

Cited by 93 publications

(76 citation statements)

References 30 publications

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“…Collagen I, in particular, is an abnormal component of the extracellular matrix not found in normal glomeruli, but present to a significant degree in glomeruli showing injury in the setting of intraglomerular hypertension (38). In MC, mechanical stress leads to the production and secretion of numerous extracellular matrix proteins including fibronectin, laminin, and collagens I and IV (6,8). Thus, the primary purpose of this study was to determine whether Akt activation in stretched MC played a role in collagen I production.…”

Section: Discussionmentioning

confidence: 99%

“…Studies have previously shown that neutralizing antibodies to TGF-␤ or its associated latent TGF-␤ binding protein inhibit stretch-induced collagen I production, as assessed by transcript levels, in MC (8,40). Furthermore, recent studies have shown that TGF-␤ is able to activate the PI3K-Akt signaling pathway in various cell lines including hepatocellular carcinoma cells, MC, and mesenchymal cells (41)(42)(43).…”

Section: Tgf-␤1 Is Important In Strain-induced Collagen I Productionmentioning

confidence: 99%

“…Several signaling pathways have been implicated in the strain-induced production of matrix proteins, including RhoA and the mitogen-activated protein kinases (MAPK) Erk, SAPK, and p38 (9 -11). Although the profibrogenic cytokines TGF-␤ and connective tissue growth factor have been shown to play an important role (8,11,12), the regulation of strain-induced matrix protein synthesis in MC is complex and remains poorly understood.…”

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confidence: 99%

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Akt Mediates Mechanical Strain-Induced Collagen Production by Mesangial Cells

Krepinsky¹,

Li²,

Chang³

et al. 2005

Journal of the American Society of Nephrology

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Increased glomerular hydrostatic pressure is an important determinant of glomerulosclerosis and can be modeled by in vitro exposure of mesangial cells to cyclic mechanical strain. Stretched mesangial cells increase extracellular matrix protein production, the hallmark of glomerulosclerosis. Recent data indicate that the serine/threonine kinase Akt may be involved in matrix modulation. Thus, Akt activation and matrix synthesis in stretched mesangial cells were studied. Exposure of mesangial cells to 1 Hz cyclic strain led to prompt Akt activation, which was biphasic to 24 h. Activation was dependent on signaling through phosphatidylinositol-3-kinase and required EGF receptor transactivation. Inhibition of signaling through the PDGF receptor, Src kinase, or cytoskeletal disruption failed to prevent strain-induced Akt activation. Collagen type 1A1 transcript expression, promoter activation, and protein secretion were increased by stretch at 24 h and were dependent on phosphatidylinositol-3 kinase. Overexpression of dominant-negative Akt inhibited strain-induced collagen 1A1 production. Conversely, overexpression of constitutively active Akt led to increased collagen 1A1 upregulation and secretion. Finally, Akt activation was observed in the glomeruli of remnant rat kidneys, a model marked by increased intraglomerular pressure. The authors conclude that mechanical strain induces Akt activation in mesangial cells through a mechanism requiring phosphatidylinositol-3-kinase and EGF receptor transactivation. Type 1 collagen production is dependent on Akt and can be induced by Akt overexpression. Akt activation is observed in remnant kidneys in vivo. Thus, the role of Akt in progression of chronic hemodynamic glomerular disease is worthy of further exploration.

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Section: Discussionmentioning

confidence: 99%

Section: Tgf-␤1 Is Important In Strain-induced Collagen I Productionmentioning

confidence: 99%

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confidence: 99%

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Akt Mediates Mechanical Strain-Induced Collagen Production by Mesangial Cells

Krepinsky¹,

Li²,

Chang³

et al. 2005

Journal of the American Society of Nephrology

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“…Endothelial cells are known to respond to shear stress and cardiac myocytes to strain with teleologically understandable alterations (Li et al, 1999a;Wung et al, 1999). As well, the response of cells of the kidney (Hirakata et al, 1997;Ingram et al, 1999) and lung (Kulik and Alvarado, 1993), to name but a few other organs, demonstrably respond to their mechanical environments. Indeed, as onecelled organisms are known to respond to pressure generated by the height of fluid in which they exist (Sukharev et al, 1997), it would seem logical that an ability to respond to the mechanical environment would be an adaptive evolutionary stress that might have affected the joining of cells into complex organisms during evolution.…”

Section: Introductionmentioning

confidence: 99%

Molecular pathways mediating mechanical signaling in bone

Rubin

Jacobs

2006

Gene

397

303

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Bone tissue has the capacity to adapt to its functional environment such that its morphology is "optimized" for the mechanical demand. The adaptive nature of the skeleton poses an interesting set of biological questions (e.g., how does bone sense mechanical signals, what cells are the sensing system, what are the mechanical signals that drive the system, what receptors are responsible for transducing the mechanical signal, what are the molecular responses to the mechanical stimuli). Studies of the characteristics of the mechanical environment at the cellular level, the forces that bone cells recognize, and the integrated cellular responses are providing new information at an accelerating speed. This review first considers the mechanical factors that are generated by loading in the skeleton, including strain, stress and pressure. Mechanosensitive cells placed to recognize these forces in the skeleton, osteoblasts, osteoclasts, osteocytes and cells of the vasculature are reviewed. The identity of the mechanoreceptor(s) is approached, with consideration of ion channels, integrins, connexins, the lipid membrane including caveolar and noncaveolar lipid rafts and the possibility that altering cell shape at the membrane or cytoskeleton alters integral signaling protein associations. The distal intracellular signaling systems on-line after the mechanoreceptor is activated are reviewed, including those emanating from G-proteins (e.g., intracellular calcium shifts), MAPKs, and nitric oxide. The ability to harness mechanical signals to improve bone health through devices and exercise is broached. Increased appreciation of the importance of the mechanical environment in regulating and determining the structural efficacy of the skeleton makes this an exciting time for further exploration of this area.

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“…In HMCs several insults, including high glucose, stretch and angiotensin II [36][37][38], induce fibronectin production via a TGF-β1-dependent mechanism. In vitro, in lung fibroblasts, TGF-β1 is the mediator of MCP-1-induced collagen I production [31].…”

Section: Discussionmentioning

confidence: 99%

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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Tyrosine kinase dependent expression of TGF-β induced by stretch in mesangial cells

Cited by 93 publications

References 30 publications

Akt Mediates Mechanical Strain-Induced Collagen Production by Mesangial Cells

Akt Mediates Mechanical Strain-Induced Collagen Production by Mesangial Cells

Molecular pathways mediating mechanical signaling in bone

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

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