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Salutary Effect of Pigment Epithelium–Derived Factor in Diabetic Nephropathy

Evidence for Antifibrogenic Activities

¹ Departments of Medicine Endocrinology and Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
² Department of Ophthalmology, Dean A. McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
³ Department of Medicine Nephrology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma

Address correspondence and reprint requests to Jian-xing Ma, MD, PhD, 941 Stanton L. Young Blvd., BSEB 328B, Oklahoma City, OK 73104. E-mail: jian-xing-ma{at}ouhsc.edu

Abbreviations: Ad-GFP, adenovirus expressing green fluorescent protein; Ad-PEDF, adenovirus expressing pigment epithelium–derived factor; CTGF, connective tissue growth factor; ECM, extracellular matrix; ELISA, enzyme-linked immunosorbent assay; GFP, green fluorescent protein; HMC, human mesangial cell; MMP-2, matrix metalloproteinase-2; PEDF, pigment epithelium–derived factor; STZ, streptozotocin; TGF-ß, transforming growth factor-ß; UAE, urine albumin excretion

Diabetic nephropathy is a major complication of diabetes and a leading cause of end-stage renal diseases in the U.S. Pigment epithelium–derived factor (PEDF) is a potent angiogenic inhibitor that has been extensively studied in diabetic retinopathy. Recently, we reported that PEDF is expressed at high levels in normal kidneys and that PEDF levels are decreased in kidneys of streptozotocin (STZ)-induced diabetic rats. In the present study, we injected STZ-diabetic rats with an adenovirus expressing PEDF (Ad-PEDF) to evaluate its effects in diabetes. The results showed that increased expression of PEDF in the kidney in response to Ad-PEDF delivery significantly alleviated microalbuminuria in early stages of diabetes. Administration of Ad-PEDF was found to prevent the overexpression of two major fibrogenic factors, transforming growth factor-ß (TGF-ß)1 and connective tissue growth factor (CTGF), and to significantly reduce the production of an extracellular matrix (ECM) protein in the diabetic kidney. Moreover, PEDF upregulated metalloproteinase-2 expression in diabetic kidney, which is responsible for ECM degradation. In cultured human mesangial cells, PEDF significantly inhibited the overexpression of TGF-ß1 and fibronectin induced by angiotensin II. PEDF also blocked the fibronectin production induced by TGF-ß1 through inhibition of Smad3 activation. These findings suggest that PEDF functions as an endogenous anti–TGF-ß and antifibrogenic factor in the kidney. A therapeutic potential of PEDF in diabetic nephropathy is supported by its downregulation in diabetes; its prevention of the overexpression of TGF-ß, CTGF, and ECM proteins in diabetic kidney; and its amelioration of proteinuria in diabetic rats following Ad-PEDF injection.

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