title: Decreased expression of pigment epithelium-derived factor is involved in the pathogenesis of diabetic nephropathy.
abstract: Pigment epithelium-derived factor (PEDF) is a potent angiogenic inhibitor. Previous studies have shown that decreased ocular levels of PEDF are associated with diabetic retinopathy. However, the implication of PEDF expression in diabetic nephropathy has not been revealed. In the present study, we demonstrated for the first time that the expression of PEDF was decreased at both the mRNA and protein levels in the kidney of diabetic rats, whereas transforming growth factor-beta (TGF-beta) and fibronectin levels were increased in the same diabetic kidneys. As shown by immunohistochemistry, the decrease of PEDF expression occurs primarily in the glomeruli. In vitro studies showed that high concentrations of glucose significantly decreased PEDF secretion in primary human glomerular mesangial cells (HMCs), suggesting that hyperglycemia is a direct cause of the PEDF decrease in the kidney. Toward the function of PEDF, we showed that PEDF blocked the high-glucose-induced overexpression of TGF-beta, a major pathogenic factor in diabetic nephropathy, and fibronectin in primary HMCs, suggesting that PEDF may function as an endogenous inhibitor of TGF-beta expression and fibronectin production in glomeruli. Therefore, decreased expression of PEDF in diabetic kidneys may contribute to extracellular matrix overproduction and the development of diabetic nephropathy.
authors.affiliation: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Wang
authors.forename: Sarah X
authors.initials: SX
authors.lastname: Zhang
authors.forename: Kangmo
authors.initials: K
authors.lastname: Lu
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Robert
authors.initials: R
authors.lastname: Mott
authors.forename: Sanai
authors.initials: S
authors.lastname: Sato
authors.forename: Jian-Xing
authors.initials: JX
authors.lastname: Ma
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D005353:Fibronectins / Q000378:metabolism; D005920:Glomerular Mesangium / Q000502:physiology / Q000503:physiopathology; D007150:Immunohistochemistry; D007668:Kidney / Q000502:physiology / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000502:physiology / Q000503:physiopathology; D009414:Nerve Growth Factors / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011914:Rats, Inbred BN; D012016:Reference Values; D015843:Serpins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000378:metabolism; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D005136:Eye Proteins; D005353:Fibronectins; D009414:Nerve Growth Factors; D015843:Serpins; D016212:Transforming Growth Factor beta; D000099174:Pigment Epithelium-Derived Factor