title: 9-cis-retinoic acid improves sensitivity to platelet-derived growth factor-BB via RXRα and SHP-1 in diabetic retinopathy.
abstract: Diabetic retinopathy (DR) is one of the most common complications of diabetes mellitus. But few efficient therapeutic methods have been reported. This study discussed the functions of 9-cis-retinoic acid (9-cis-RA) in sensitizing retinal pericytes to platelet-derived growth factor (PDGF)-BB. Using streptozotocin (STZ)-induced diabetic mice and high glucose-treated bovine retinal pericytes (BRPC), we analyzed the impacts of 9-cis-RA by detecting cell apoptosis via DNA fragmentation assay and detecting related factors through adenovirus or lentivirus infection and western blot. Results showed that in retinas of STZ-induced diabetic mice, 9-cis-RA significantly inhibited expression of SHP-1 (P < 0.01), thus promoting p-AKT and p-ERK1/2, which reflected the improved sensitivity to PDGF-BB. In BRPC, 9-cis-RA also improved sensitivity to PDGF-BB and suppressed cell apoptosis (P < 0.01) via down-regulating SHP-1. Further mechanism analyses showed that the efficient functioning of 9-cis-RA relied on the existence of its receptor, retinoic X receptor α (RXRα), independent of the previous reported protein kinase C delta (PKCδ)/SHP-1 axis. Because 9-cis-RA could not inhibit SHP-1 or improve sensitivity to PDGF-BB when RXRα was knocked down, while it still suppressed SHP-1 after overexpression of PKCδ. Taken together, these results indicated the vital roles of 9-cis-RA in improving sensitivity to PDGF-BB of retinal pericytes in DR, and provided basic evidences of new therapeutic targets like RXRα for further DR treatment.
authors: The Third Xiangya Hospital Central South University, Changsha, Hunan 410013, China; The Second Xiangya Hospital Central South University, Changsha, Hunan 410011, China.
authors: Yu
authors: Y
authors: Chen
authors: Department of Cardio-Thoracic Surgery, Hunan Provincial People's Hospital, Changsha, Hunan 410005, China.
authors: Wen
authors: W
authors: Wang
authors: Department of Gynecology and Obstetrics, Tai He Hospital, Changsha, Hunan 410000, China.
authors: Fen
authors: F
authors: Liu
authors: The Second Xiangya Hospital Central South University, Changsha, Hunan 410011, China.
authors: Luosheng
authors: L
authors: Tang
authors: The Third Xiangya Hospital Central South University, Changsha, Hunan 410013, China.
authors: Renhong
authors: R
authors: Tang
authors: The Third Xiangya Hospital Central South University, Changsha, Hunan 410013, China. Electronic address: liwenjie336@126.com.
authors: Wenjie
authors: W
authors: Li
mesh_terms: D000077556:Alitretinoin; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000077214:Becaplermin; D002417:Cattle; D002478:Cells, Cultured; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020286:Pericytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D047490:Retinoid X Receptor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D020574:Proto-Oncogene Proteins c-sis; D034741:RNA, Small Interfering; D047490:Retinoid X Receptor alpha; D000077214:Becaplermin; D000077556:Alitretinoin; D014212:Tretinoin; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse; D005947:Glucose
keywords: 9-cis-retinoic acid; Diabetic retinopathy; Platelet-derived growth factor; Protein phosphatase regulator SHP-1; Retinoic X receptor