title: Poly(ADP-ribose) polymerase is involved in the development of diabetic retinopathy via regulation of nuclear factor-kappaB.
abstract: The current study investigated the role of poly(ADP-ribose) polymerase (PARP) in the development of diabetic retinopathy. Activity of PARP was increased in whole retina and in endothelial cells and pericytes of diabetic rats. Administration of PJ-34 (a potent PARP inhibitor) for 9 months to diabetic rats significantly inhibited the diabetes-induced death of retinal microvascular cells and the development of early lesions of diabetic retinopathy, including acellular capillaries and pericyte ghosts. To further investigate how PARP activation leads to cell death in diabetes, we investigated the possibility that PARP acts as a coactivator of nuclear factor-kappaB (NF-kappaB) in the retinal cells. In bovine retinal endothelial cells (BRECs), PARP interacted directly with both subunits of NF-kappaB (p50 and p65). More PARP was complexed to the p50 subunit in elevated glucose concentration (25 mmol/l) than at 5 mmol/l glucose. PJ-34 blocked the hyperglycemia-induced increase in NF-kappaB activation in BRECs. PJ-34 also inhibited diabetes-induced increase expression of intercellular adhesion molecule-1, a product of NF-kappaB-dependent transcription in retina, and subsequent leukostasis. Inhibition of PARP or NF-kappaB inhibited the hyperglycemia (25 mmol/l glucose)-induced cell death in retinal endothelial cells. Thus, PARP activation plays an important role in the diabetes-induced death of retinal capillary cells, at least in part via its regulation of NF-kappaB.
authors.affiliation: Department of Pharmacology, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Zheng
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabó
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Kern
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis; D002417:Cattle; D016923:Cell Death; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003930:Diabetic Retinopathy / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000473:pathology / Q000502:physiology* / Q000503:physiopathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics*; D051381:Rats; D011917:Rats, Inbred Lew; D012171:Retinal Vessels
chemical_list: D017304:Annexin A5; D016328:NF-kappa B; D011065:Poly(ADP-ribose) Polymerases