Overexpression of Urokinase by Macrophages or Deficiency of Plasminogen Activator Inhibitor Type 1 Causes Cardiac Fibrosis in Mice

Moriwaki, Hisataka; Stempien‐Otero, April; Kremen, Michal; Cozen, Aaron E.; Dichek, David A.

doi:10.1161/01.res.0000141427.61023.f4

Cited by 106 publications

(113 citation statements)

References 47 publications

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“…Plasminogen activator inhibitor-1 deficiency was shown to protect against combined AngII and aldosterone-induced remodeling in the aortas but enhance AngII and aldosterone as well as senescent fibrosis in the heart. 35,36 It should be noted that the Masson staining for collagen in this study was expressed as a fraction of Oil-Red-O staining for lipids, and additional biochemical measurements (i.e., HPLC-determined collagen) revealed no difference in the absolute collagen content of aortas from untreated and losartan-treated mice. Taken together, the data indicate that the relative increase in Masson staining for collagen in losartan-treated mice may reflect a greater contribution of decreased lipids induced by losartan than an absolute increase in the plaque or vessel wall collagen.…”

Section: Discussionmentioning

confidence: 69%

Angiotensin Inhibition Decreases Progression of Advanced Atherosclerosis and Stabilizes Established Atherosclerotic Plaques

Suganuma¹,

Babaev²,

Motojima³

et al. 2007

Journal of the American Society of Nephrology

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Although increased extracellular matrix (ECM) is pathogenic in a variety of chronic tissue injuries, reduced and/or disrupted ECM may be detrimental in atherosclerosis and rather destabilize existing atherosclerotic lesions. This study therefore assessed the effects of angiotensin II (AngII) antagonism on ECM components of advanced atherosclerosis. Twenty-four-week-old apolipoprotein E-deficient mice were treated with the AngII antagonist losartan for 12 wk. Controls received water or hydralazine. AngII antagonism significantly reduced progression of established atherosclerosis, whereas hydralazine showed no benefit despite similar decrease in BP. Although there was no difference in the macrophage component, AngII antagonism increased the relative collagen portion of the lesions; lessened elastin fragmentation, increased the total elastin content of the aorta; and reduced the mRNA and activity/ protein of the elastolytic proteases, cathepsin S, and metalloproteinase-9. Extracellular elastin degradation by cultured smooth muscle cells (SMC) was reduced by losartan, as was SMC invasion through an elastin gel barrier. Thus, AngII antagonism lessens progression of atherosclerosis, increases collagen, and preserves elastin components of ECM within the vascular lesions, which, at least in part, is modulated by effects on SMC. These effects not only decrease further expansion of advanced lesions but also stabilize the established atherosclerotic plaques and may underlie the decreased incidence of acute cardiovascular events that are observed in patients in whom AngII antagonism is begun after atherosclerosis is already established.

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Section: Discussionmentioning

confidence: 69%

Angiotensin Inhibition Decreases Progression of Advanced Atherosclerosis and Stabilizes Established Atherosclerotic Plaques

Suganuma¹,

Babaev²,

Motojima³

et al. 2007

Journal of the American Society of Nephrology

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“…PAI-1-deficient nondiabetic mice developed increased immunostaining for TGFB1, increased cortical α-Sma mRNA and protein, as well as increased interstitial area. While these results were unexpected given the protection that PAI-1 deficiency conferred on diabetic mice, aged PAI-1-deficient mice develop cardiac fibrosis [44], despite being protected from pathogenetic fibrosis post cardiac ischaemia [12]. PAI-1 participates both as a key effector molecule in fibrotic processes, including those driven by TGFB1, [45], and potentially as a negative regulator of TGFB1 [46].…”

Section: Discussionmentioning

confidence: 98%

Plasminogen activator inhibitor-1 production is pathogenetic in experimental murine diabetic renal disease

et al. 2007

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Aims/hypothesis Plasminogen activator inhibitor-1 (PAI-1, also known as serpin peptidase inhibitor, clade E [nexin, plasminogen activator inhibitor type 1], member 1 [SERPINE1]) plays a pathogenetic role in renal fibrosis. It is upregulated in experimental and human diabetic nephropathy. These studies assessed the effect of PAI-1 deficiency and overproduction on renal disease in experimental diabetes. Materials and methods Diabetes was induced by injection of streptozotocin in 6-week-old PAI-1-deficient mice, transgenic mice overexpressing Pai-1 and control mice.Animals were killed after 24 weeks of diabetes or after observation alone. Results Pai-1 mRNA was upregulated in kidneys from genetically normal mice with diabetes and in non-diabetic Pai-1 transgenic mice. PAI-1 was not further increased in kidneys from Pai-1 transgenic mice with diabetes. Diabetes-associated albuminuria and glomerular injury, as well as renal α-smooth muscle actin production, were ameliorated in diabetic PAI-1-deficient mice, an amelioration associated with attenuated increases in renal matrix metallopeptidase-2 expression and activity. Diabetic Pai-1 transgenic mice did not develop increased albuminuria or glomerular injury, but the tubulointerstitial area was modestly enhanced. In addition to the findings in diabetic mice, abnormalities also developed in 30-week-old PAI-1-deficient and Pai-1 transgenic mice without diabetes. PAI-1 deficiency resulted in increased tubulointerstitial area, TGFB1 protein and α-smooth muscle actin. Non-diabetic 30-week-old Pai-1 transgenic mice developed similar renal abnormalities and increased matrix metallopeptidase-2 activity, together with a modest increase in serum glucose and HbA 1c . Conclusions/interpretation These results demonstrate that endogenous PAI-1 deficiency protects mice from glomerular injury in longer term diabetes and that endogenous PAI-1 maintains normal renal interstitial structure in ageing not associated with diabetes.

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“…In contrast uPA deficiency worsened bleomycin-induced lung fibrosis and significantly reduced fibrosis in hearts that were damaged by viral myocarditis or left ventricular pressure overload (113,117,118). Delivery of exogenous uPA as a recombinant protein or via an uPA-expressing viral vector reduced fibrosis in the lung and liver while mice with macrophages engineered to overexpress uPA spontaneously developed cardiac fibrosis (119)(120)(121)(122). In chronic renal tubulointerstitial disease the induction of endogenous uPAR reduces fibrosis severity while in a model of crescentic glomerulonephritis, genetic deficiency of either uPA or uPAR did not worsen glomerulosclerosis although the degree of glomerular inflammation was reduced in the uPAR−/− mice (22,50).…”

Section: Role Of Upa and Upar During Fibrogenesis: Disease And Organ mentioning

confidence: 99%

Urokinase and its receptors in chronic kidney disease

Zhang

Eddy

2008

Front Biosci

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Since the recognition that plasminogen activator inhibitor-1 (PAI-1) is a powerful profibrotic molecule, there has been considerable interest in deciphering the extent to which this effect is mediated by its ability to inhibit serine proteases with downstream effects on fibrogenesis. This review will summarize current knowledge about the serine protease urokinase-type plasminogen activator and its high affinity receptor uPAR/CD87 as it pertains to chronic kidney disease (CKD) progression. An emerging theme is that the effects of PAI-1 and uPAR appear to be organ-and site-specific. Normal kidney tubules produce a large quantity of uPA that is secreted into the urinary space. Activity levels increase during CKD presumably due to new sources of production by macrophages and fibroblasts. By activating hepatocyte growth factor and degrading fibrinogen uPA may have anti-fibrotic effects. However CKD severity after experimental ureteral obstruction is not altered by endogenous uPA deficiency. Beneficial effects of exogenous uPA have been reported in experimental models of fibrosis in the lung and liver but CKD awaits exploration.Absent in normal kidneys uPAR is expressed by both renal parenchymal cells and inflammatory cells in a variety of pathological states. Such expression appears beneficial based on studies performed in uPAR-deficient mice. The uPAR promotes bacterial clearance in infectious diseases. In CKD uPAR expression is associated with high uPA activity but its most important effect appears to be due to scavenging activities and effects on cell recruitment and migration. Although uPAR itself is a non-signaling receptor, it interacts with a variety of co-receptors to modify cellular behavior. Best known are interactions with the low-density lipoprotein receptor-related protein (LRP-1) that lead to PAI-1 endocytosis and degradation, and interactions with several integrins to regulate matrix-dependent cell migration. Contacts with the receptor for the complement C5a component and the interleukin −6 receptor gp130 are examples of other recently recognized interactions.In addition to uPA, vitronectin and high molecular weight kininogen are alternate uPAR ligands that could be implicated in CKD progression. uPAR may also be shed from cell membranes. This soluble form (suPAR) has been detected in plasma and urine and is known to be a chemoattractant for leukocytes that express the formyl-peptide-receptor-like receptor

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Overexpression of Urokinase by Macrophages or Deficiency of Plasminogen Activator Inhibitor Type 1 Causes Cardiac Fibrosis in Mice

Cited by 106 publications

References 47 publications

Angiotensin Inhibition Decreases Progression of Advanced Atherosclerosis and Stabilizes Established Atherosclerotic Plaques

Angiotensin Inhibition Decreases Progression of Advanced Atherosclerosis and Stabilizes Established Atherosclerotic Plaques

Plasminogen activator inhibitor-1 production is pathogenetic in experimental murine diabetic renal disease

Urokinase and its receptors in chronic kidney disease

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