title: An additive effect of anti-PAI-1 antibody to ACE inhibitor on slowing the progression of diabetic kidney disease.
abstract: While angiotensin II blockade slows the progression of diabetic nephropathy, current data suggest that it alone cannot stop the disease process. New therapies or drug combinations will be required to further slow or halt disease progression. Inhibition of plasminogen activator inhibitor type 1 (PAI-1) aimed at enhancing ECM degradation has shown therapeutic potential in diabetic nephropathy. Here, using a mouse model of type diabetes, the maximally therapeutic dose of the PAI-1-neutralizing mouse monoclonal antibody (MEDI-579) was determined and compared with the maximally effective dose of enalapril. We then examined whether addition of MEDI-579 to enalapril would enhance the efficacy in slowing the progression of diabetic nephropathy. Untreated uninephrectomized diabetic db/db mice developed progressive albuminuria and glomerulosclerosis associated with increased expression of transforming growth factor (TGF)-β1, PAI-1, type IV collagen, and fibronectin from weeks 18 to 22, which were reduced by MEDI-579 at 3 mg/kg body wt, similar to enalapril given alone from weeks 12 to 22 Adding MEDI-579 to enalapril from weeks 18 to 22 resulted in further reduction in albuminuria and markers of renal fibrosis. Renal plasmin generation was dramatically reduced by 57% in diabetic mice, a decrease that was partially reversed by MEDI-579 or enalapril given alone but was further restored by these two treatments given in combination. Our results suggest that MEDI-579 is effective in slowing the progression of diabetic nephropathy in db/db mice and that the effect is additive to ACEI. While enalapril is renal protective, the add-on PAI-1 antibody may offer additional renoprotection in progressive diabetic nephropathy via enhancing ECM turnover.
authors: Department of Pathology, School of Medicine and Life Science, Nanjing University of Chinese Medicine, Nanjing, China.|Division of Nephrology, University of Utah, Salt Lake City, Utah; and.
authors: Chunyan
authors: C
authors: Gu
authors: Division of Nephrology, University of Utah, Salt Lake City, Utah; and.
authors: Jiandong
authors: J
authors: Zhang
authors: Division of Nephrology, University of Utah, Salt Lake City, Utah; and.
authors: Nancy A
authors: NA
authors: Noble
authors: Bioscience, AstraZeneca R&D, Pepparredsleden 1, Molndal SE-43183, Sweden.
authors: Xiao-Rong
authors: XR
authors: Peng
authors: Division of Nephrology, University of Utah, Salt Lake City, Utah; and Yufeng.huang@hsc.utah.edu.
authors: Yufeng
authors: Y
authors: Huang
mesh_terms: D000419:Albuminuria / Q000188:drug therapy* / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000627:therapeutic use*; D024141:Collagen Type IV / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism; D018450:Disease Progression; D004359:Drug Therapy, Combination; D004656:Enalapril / Q000627:therapeutic use*; D005341:Fibrinolysin / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D017395:Plasminogen Activator Inhibitor 1 / Q000276:immunology* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D057134:Antibodies, Neutralizing; D024141:Collagen Type IV; D005353:Fibronectins; D017395:Plasminogen Activator Inhibitor 1; D053773:Transforming Growth Factor beta1; D004656:Enalapril; D005341:Fibrinolysin
keywords: PAI-1; TGF-β1; diabetic nephropathy; enalapril