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A PAI-1 Mutant, PAI-1R, Slows Progression of Diabetic Nephropathy

Yufeng Huang^*, Wayne A. Border^*, Ling Yu^*, Jiandong Zhang^*, Daniel A. Lawrence and Nancy A. Noble^*

^* Fibrosis Research Laboratory, Division of Nephrology, University of Utah School of Medicine, Salt Lake City, Utah; and Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan

Correspondence: Dr. Nancy A. Noble, Fibrosis Research Laboratory, 391 Chipeta Way, Suite E, Salt Lake City, UT 84108. Phone: 801-581-4615; Fax: 801-585-0579; E-mail: Nancy.noble{at}hsc.utah.edu

Received for publication April 26, 2007. Accepted for publication October 17, 2007.

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 1(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.

This article has been cited by other articles:

				J. Zhang, N. A. Noble, W. A. Border, R. T. Owens, and Y. Huang Receptor-dependent prorenin activation and induction of PAI-1 expression in vascular smooth muscle cells Am J Physiol Endocrinol Metab, October 1, 2008; 295(4): E810 - E819. [Abstract] [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673