A PAI-1 mutant, PAI-1R, slows progression of diabetic nephropathy.
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.
Huang
Yufeng
Y
Fibrosis Research Laboratory, Division of Nephrology, University of Utah School of Medicine, Salt Lake City, Utah 84108, USA.
Border
Wayne A
WA
Yu
Ling
L
Zhang
Jiandong
J
Lawrence
Daniel A
DA
Noble
Nancy A
NA
D000818:Animals; D003094:Collagen / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005341:Fibrinolysin / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics* / Q000378:metabolism / Q000493:pharmacokinetics; D011507:Proteinuria / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D017395:Plasminogen Activator Inhibitor 1; D053773:Transforming Growth Factor beta1; D003094:Collagen; D005341:Fibrinolysin