Abstract
Plasminogen activator inhibitor-1 (PAI-1) has been implicated in renal fibrosis. In vitro, PAI-1 inhibits plasmin generation, and this decreases mesangial extracellular matrix turnover. PAI-1R, a mutant PAI-1, increases glomerular plasmin generation, reverses PAI-1 inhibition of matrix degradation, and reduces disease in experimental glomerulonephritis. This study sought to determine whether short-term administration of PAI-1R could slow the progression of glomerulosclerosis in the db/db mouse, a model of type 2 diabetes in which mesangial matrix accumulation is evident by 20 wk of age. Untreated uninephrectomized db/db mice developed progressive albuminuria and mesangial matrix expansion between weeks 20 and 22, associated with increased renal mRNA encoding alpha1(I) and (IV) collagens and fibronectin. Treatment with PAI-1R prevented these changes without affecting body weight, blood glucose, glycosylated hemoglobin, creatinine, or creatinine clearance; therefore, PAI-1R may prevent progression of glomerulosclerosis in type 2 diabetes.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Collagen / metabolism
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Diabetes Mellitus, Type 2 / complications*
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Diabetic Nephropathies / drug therapy
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Diabetic Nephropathies / pathology*
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Diabetic Nephropathies / physiopathology*
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Disease Models, Animal
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Disease Progression
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Dose-Response Relationship, Drug
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Extracellular Matrix / drug effects
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Extracellular Matrix / metabolism
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Extracellular Matrix / pathology
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Extracellular Matrix Proteins / genetics
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Extracellular Matrix Proteins / metabolism
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Fibrinolysin / metabolism
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Fibronectins / metabolism
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Glomerular Mesangium / drug effects
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Glomerular Mesangium / metabolism
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Glomerular Mesangium / pathology
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Injections, Intraperitoneal
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Kidney / drug effects
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Kidney / metabolism
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Kidney / pathology
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Kidney Cortex / drug effects
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Kidney Cortex / metabolism
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Kidney Cortex / pathology
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Mice
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Mice, Mutant Strains
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Plasminogen Activator Inhibitor 1 / genetics*
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Plasminogen Activator Inhibitor 1 / metabolism
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Plasminogen Activator Inhibitor 1 / pharmacokinetics
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Proteinuria / drug therapy
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Proteinuria / pathology
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Proteinuria / physiopathology
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Transforming Growth Factor beta1 / genetics
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Transforming Growth Factor beta1 / metabolism
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Up-Regulation / drug effects
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Up-Regulation / physiology
Substances
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Extracellular Matrix Proteins
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Fibronectins
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Plasminogen Activator Inhibitor 1
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Transforming Growth Factor beta1
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Collagen
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Fibrinolysin