Regulation of extracellular matrix by mechanical stress in rat glomerular mesangial cells.

Yasuda, Tadashi; Kondo, Sylvia; Homma, Teiichi; Harris, Raymond C.

doi:10.1172/jci119003

Cited by 140 publications

(108 citation statements)

References 45 publications

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“…Mechanical stretch has been shown to increase TGF-␤1 production and secretion in MC and other cells (7,8,73), and this cytokine plays an important role in stretch-induced upregulation of matrix proteins including collagen I (8,74). Our data have further demonstrated that collagen I protein secretion into the medium also requires the autocrine action of TGF-␤1.…”

Section: Discussionsupporting

confidence: 63%

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: Discussionsupporting

confidence: 63%

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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“…On the other hand, mechanical stretch and high glucose directly stimulate Tgfb1 expression and TGFB1 production in cultured mesangial cells, resulting in collagen accumulation [33][34][35][36]. These results indicate that metabolic and haemodynamic changes may also induce extracellular matrix accumulation independently of inflammation in the development of diabetic glomerulosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Erythromycin ameliorates renal injury via anti-inflammatory effects in experimental diabetic rats

et al. 2005

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Aims/hypothesis: Recent studies have shown that the inflammatory process is involved in the pathogenesis of diabetic nephropathy. Fourteen-membered ring macrolides, including erythromycin, have anti-inflammatory, as well as antibacterial effects. The aim of this study was to investigate the renoprotective effects of erythromycin in streptozotocin (STZ)-induced diabetic rats. Methods: STZinduced diabetic rats were treated orally with erythromycin (5 mg/kg body weight) or vehicle every day for 8 weeks.To evaluate the effect of erythromycin treatment, we measured urinary albumin excretion, and examined the following in the kidney: histological changes, the expression of intercellular adhesion molecule-1 (ICAM-1), macrophage infiltration, and nuclear factor-kappa B (NF-κB) activity. Results: Erythromycin significantly reduced urinary albumin excretion without affecting blood glucose levels and blood pressure. Erythromycin also attenuated glomerular hypertrophy, mesangial expansion, macrophage infiltration and ICAM-1 expression in renal tissues. The expression of the gene encoding TGFB1 (also known as TGF-β1), type IV collagen protein production and NF-κB activity in renal tissues were increased in diabetic rats and reduced by erythromycin treatment. Conclusions/ interpretation: Erythromycin prevented renal injuries without changes of blood glucose levels and blood pressure in experimental diabetic rats. These results suggest that the renoprotective effects of erythromycin are based on its anti-inflammatory effect via suppression of NF-κB activation. Modulation of microinflammation with erythromycin may provide a new approach for diabetic nephropathy.

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“…It has been shown that mesangial cells exposed to continuous cycles of stretch/relaxation increase gene and/ or protein expression of extracellular matrix components, including fibronectin, collagen I, III and IV and laminin. 39 Furthermore, this accumulation of extracellular matrix, which occurs as a result of mechanical stretch, is markedly enhanced in a milieu of high glucose concentration. 40 Of interest here is that mechanical stretch may promote extracellular matrix accumulation in cultured mesangial cells, not only by increasing synthesis of extracellular matrix components, but also by decreasing the activity of degradative enzymes.…”

Section: In Vitro Studies Searching For the Mechanism Of The Interactmentioning

confidence: 99%

“…40 Of interest here is that mechanical stretch may promote extracellular matrix accumulation in cultured mesangial cells, not only by increasing synthesis of extracellular matrix components, but also by decreasing the activity of degradative enzymes. 39 In addition, mechanical stretch induces both gene and protein expression of transforming growth factor (TGF)-b1, 39,41 a cytokine involved in the accumulation of extracellular matrix in diabetic nephropathy. 41 Mechanical stretch has also been shown to induce gene expression, but not protein secretion of connective growth factor, a downstream mediator of TGF-b1 signaling.…”

Section: In Vitro Studies Searching For the Mechanism Of The Interactmentioning

confidence: 99%

The contribution of hypertension to diabetic nephropathy and retinopathy: the role of inflammation and oxidative stress

2011

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Diabetes and hypertension frequently coexist and constitute the most notorious combination for the pathogenesis of diabetic nephropathy and retinopathy. Large clinical trials have clearly demonstrated that tight control of glycemia and/or blood pressure significantly reduces the incidence and progression of diabetic retinopathy (DR) and nephropathy. However, the mechanism by which hypertension interacts with diabetes to induce and/or exacerbate nephropathy and retinopathy is very unclear. Substantial evidence implicates the involvement of chronic inflammation and oxidative stress in the pathogenesis of DR and nephropathy. In addition, hypertension causes oxidative stress and inflammation in the kidney and retina. In the present review, we summarized data obtained from our research along with those from other groups to better understand the role of hypertension in the pathogenesis of diabetic nephropathy and retinopathy. It is suggested that oxidative stress and inflammation may be common denominators of kidney and retinal damage in the concomitant presence of diabetes and hypertension.

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Regulation of extracellular matrix by mechanical stress in rat glomerular mesangial cells.

Cited by 140 publications

References 45 publications

Akt Mediates Mechanical Strain-Induced Collagen Production by Mesangial Cells

Akt Mediates Mechanical Strain-Induced Collagen Production by Mesangial Cells

Erythromycin ameliorates renal injury via anti-inflammatory effects in experimental diabetic rats

The contribution of hypertension to diabetic nephropathy and retinopathy: the role of inflammation and oxidative stress

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