title: PEDF inhibits AGE-induced podocyte apoptosis via PPAR-gamma activation.
abstract: Advanced glycation end products (AGEs) formed at an accelerated rate under diabetes, elicit oxidative and pro-apoptotic reactions in various types of cells, including podocytes, thus being involved in the development and progression of diabetic nephropathy. Recently, we, along with others, have found that pigment epithelium-derived factor (PEDF), a glycoprotein with potent neuronal differentiating activity, inhibits AGE-elicited mesangial and tubular cell damage through its anti-oxidative properties. However, the effects of PEDF on podocyte loss, one of the characteristic features of diabetic nephropathy remain unknown. In this study, we investigated whether and how PEDF could protect against AGE-elicited podocyte apoptosis in vitro. AGEs decreased PEDF mRNA level in podocytes, which was blocked by neutralizing antibody raised against receptor for AGEs (RAGE-Ab). PEDF or RAGE-Ab was found to inhibit the AGE-induced up-regulation of RAGE mRNA level, oxidative stress generation and resultant apoptosis in podocytes. All of the beneficial effects of PEDF on AGE-exposed podocytes were blocked by the treatment of GW9662, an inhibitor of peroxisome proliferator-activated receptor-γ (PPARγ). Further, although PEDF did not affect protein expression levels of PPARγ, it significantly restored the PPARγ transcriptional activity in AGE-exposed podocytes. The present results demonstrated for the first time that PEDF could block the AGE-induced apoptotic cell death of podocytes by suppressing RAGE expression and subsequent ROS generation partly via PPARγ activation. Our present study suggests that substitution of PEDF proteins may be a promising strategy for preventing the podocyte loss in diabetic nephropathy.
authors.affiliation: Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishibashi
authors.forename: Takanori
authors.initials: T
authors.lastname: Matsui
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ohta
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Tanoue
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Asanuma
authors.forename: Kei
authors.initials: K
authors.lastname: Fukami
authors.forename: Seiya
authors.initials: S
authors.lastname: Okuda
authors.forename: Kei-ichiro
authors.initials: K
authors.lastname: Nakamura
authors.forename: Sho-ichi
authors.initials: S
authors.lastname: Yamagishi
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002417:Cattle; D002454:Cell Differentiation; D004996:Ethidium / Q000031:analogs & derivatives / Q000494:pharmacology; D005136:Eye Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism; D051379:Mice; D009414:Nerve Growth Factors / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D050199:Podocytes / Q000166:cytology*; D012333:RNA, Messenger / Q000378:metabolism; D015843:Serpins / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D000813:Anilides; D004996:Ethidium; D005136:Eye Proteins; D017127:Glycation End Products, Advanced; D006023:Glycoproteins; D009414:Nerve Growth Factors; D047495:PPAR gamma; D012333:RNA, Messenger; D015843:Serpins; D012710:Serum Albumin, Bovine; D000099174:Pigment Epithelium-Derived Factor; C457499:2-chloro-5-nitrobenzanilide; C067883:dihydroethidium