Plasminogen Activator Inhibitor-1 in Chronic Kidney Disease

Eddy, Allison A.; Fogo, Agnes B.

doi:10.1681/asn.2006050503

Cited by 211 publications

(200 citation statements)

References 149 publications

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“…However, myostatin was found to induce this switch in the overall multipotent and myofibroblast cell populations, as indicated by the stimulation in most cells within the culture of the expression TGF-b1 and another key profibrotic factor, PAI-1 (Eddy & Fogo 2006), and particularly by the ultimate products that define fibrosis -collagens I, III, and other isoforms (Bhogal et al 2005, Attallah et al 2007.…”

Section: Discussionmentioning

confidence: 99%

Myostatin promotes a fibrotic phenotypic switch in multipotent C3H 10T1/2 cells without affecting their differentiation into myofibroblasts

Artaza¹,

Singh²,

Ferrini³

et al. 2007

Journal of Endocrinology

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Tissue fibrosis, the excessive deposition of collagen/extracellular matrix combined with the reduction of the cell compartment, defines fibroproliferative diseases, a major cause of death and a public health burden. Key cellular processes in fibrosis include the generation of myofibroblasts from progenitor cells, and the activation or switch of already differentiated cells to a fibrotic synthetic phenotype. Myostatin, a negative regulator of skeletal muscle mass, is postulated to be involved in muscle fibrosis. We have examined whether myostatin affects the differentiation of a multipotent mesenchymal mouse cell line into myofibroblasts, and/or modulates the fibrotic phenotype and Smad expression of the cell population. In addition, we investigated the role of follistatin in this process. Incubation of cells with recombinant myostatin protein did not affect the proportion of myofibroblasts in the culture, but significantly upregulated the expression of fibrotic markers such as collagen and the key profibrotic factors transforming growth factor-b1 (TGF-b1) and plasminogen activator inhibitor (PAI-1), as well as Smad3 and 4, and the pSmad2/3. An antifibrotic process evidenced by the upregulation of follistatin, Smad7, and matrix metalloproteinase 8 accompanied these changes. Follistatin inhibited TGF-b1 induction by myostatin. Transfection with a cDNA expressing myostatin upregulated PAI-1, whereas an shRNA against myostatin blocked this effect. In conclusion, myostatin induced a fibrotic phenotype without significantly affecting differentiation into myofibroblasts. The concurrent endogenous antifibrotic reaction confirms the view that phenotypic switches in multipotent and differentiated cells may affect the progress or reversion of fibrosis, and that myostatin pharmacological inactivation may be a novel therapeutic target against fibrosis.

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Section: Discussionmentioning

confidence: 99%

Myostatin promotes a fibrotic phenotypic switch in multipotent C3H 10T1/2 cells without affecting their differentiation into myofibroblasts

Artaza¹,

Singh²,

Ferrini³

et al. 2007

Journal of Endocrinology

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“…On the other hand, the ECM is normally continually degraded and accumulation of ECM may also result from a deficit in ECM degradation. The plasminogen activation system is one of the most important degrading systems for the ECM (Eddy et al, 2006;Fogo, 2003) and several studies have shown that synthesis and deposition of the inhibitory protein PAI-1 are increased in the kidney during experimental and human nephropathies (Rerolle et al, 2000;Eddy et al, 2006;Seo et al, 2009). PAI-1 is also one of the targets regulated by TGF-b1 (Keeton et al, 1991).…”

Section: Figurementioning

confidence: 99%

Honokiol ameliorates renal fibrosis by inhibiting extracellular matrix and pro‐inflammatory factors in vivo and in vitro

Chiang

Sheu

Lin

et al. 2011

British J Pharmacology

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BACKGROUND AND PURPOSE Renal fibrosis acts as the common pathway leading to the development of end-stage renal disease. The present study investigated, in vivo and in vitro, the anti-fibrotic and anti-inflammatory effects, particularly on the epithelial to mesenchymal transition of renal tubular cells, exerted by honokiol, a phytochemical used in traditional medicine, and mechanisms underlying these effects. EXPERIMENTAL APPROACH Anti-fibrotic effects in vivo were assayed in a rat model of renal fibrosis [the unilateral ureteral obstruction (UUO) model]. A rat tubular epithelial cell line (NRK-52E) was stimulated by transforming growth factor-beta 1 (TGF-beta 1) and treated with honokiol to explore possible mechanisms of these anti-fibrotic effects. Gene or protein expression was analysed by Northern or Western blotting. Transcriptional regulation was investigated using luciferase activity driven by a connective tissue growth factor (CTGF) promoter. KEY RESULTS Honokiol slowed development of renal fibrosis both in vivo and in vitro. Honokiol treatment attenuated tubulointerstitial fibrosis and expression of pro-fibrotic factors in the UUO model. Honokiol also decreased expression of the mRNA for the chemokine CCL2 and for the intracellular adhesion molecule-1, as well as accumulation of type I (alpha 1) collagen and fibronectin in UUO kidneys. Phosphorylation of Smad-2/3 induced by TGF-beta 1 and CTGF luciferase activity in renal tubular cells were also inhibited by honokiol. CONCLUSIONS AND IMPLICATIONS Honokiol suppressed expression of pro-fibrotic and pro-inflammatory factors and of extracellular matrix proteins. Honokiol may become a therapeutic agent to prevent renal fibrosis

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Section: Introductionmentioning

confidence: 99%

“…PAI-1 is a 50 kD single chain glycoprotein, upregulated by various stimuli including transforming growth factor-β1 (TGF-β1), and activated and stabilized by binding to vitronectin [7][8][9][10]. In the normal human kidney, PAI-1 is undetectable in the basal level but the expression is upregulated in several acute and chronic kidney diseases [9,10] including diabetic nephropathy [11]. A functional role of PAI-1 in renal diseases was established mainly by in vivo studies using PAI-1 knock out (KO) mice; renal fibrosis in crescentic glomerulonephritis [12], unilateral ureteral obstruction [13], and diabetic nephropathy [14][15][16] was attenuated in PAI-1 KO mice.…”

Section: Introductionmentioning

confidence: 99%

Plasminogen Activator Inhibitor-1 Antisense Oligodeoxynucleotides Abrogate Mesangial Fibronectin Accumulation

Park

Seo

2010

Korean J Physiol Pharmacol

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Plasminogen Activator Inhibitor-1 in Chronic Kidney Disease

Cited by 211 publications

References 149 publications

Myostatin promotes a fibrotic phenotypic switch in multipotent C3H 10T1/2 cells without affecting their differentiation into myofibroblasts

Myostatin promotes a fibrotic phenotypic switch in multipotent C3H 10T1/2 cells without affecting their differentiation into myofibroblasts

Honokiol ameliorates renal fibrosis by inhibiting extracellular matrix and pro‐inflammatory factors in vivo and in vitro

Plasminogen Activator Inhibitor-1 Antisense Oligodeoxynucleotides Abrogate Mesangial Fibronectin Accumulation

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