title: Reactive oxygen species enhances endothelin-1 production of diabetic rat glomeruli in vitro and in vivo.
abstract: Both reactive oxygen species (ROS) and endothelin-1 (ET- 1) have been implicated in the pathophysiology of diabetic nephropathy. The interrelationship between them, however, has not been documented in this disease. To determine whether ROS regulates ET-1 production in diabetic kidneys, we examined the in vitro and in vivo effects of ROS donors and scavengers on ET-1 production of diabetic rat glomeruli. For in vitro study, the glomeruli were isolated with a sieving method from streptozotocin-induced diabetic rats and killed at 1 week, 1 month, and 3 months, respectively. Superoxide was measured by a spectrophotometer, and ET-1 was measured by radioimmunoassay. The results demonstrated that the basal production levels of superoxide and ET-1 were higher in diabetic glomeruli than in normal glomeruli in vitro. There was a positive correlation between the production of superoxide and ET-1 in diabetic glomeruli. The basal ET-1 production was markedly attenuated by ROS scavengers including superoxide dismutase, catalase, dimethyl sulfoxide, and deferoxamine in diabetic glomeruli. Exogenous ROS generated by xanthine/xanthine oxidase significantly enhanced ET-1 generation by both diabetic and normal glomeruli. A high glucose concentration (500 mg/dL) in vitro increased ET-1 production by normal glomeruli but not diabetic glomeruli, and insulin partly suppressed ET- 1 production by diabetic glomeruli. The in vivo study demonstrated that when diabetic rats were injected daily with superoxide dismutase or catalase after diabetes was induced, the basal production of ET-1 was markedly attenuated after 1 week and 1 month, respectively. These results indicate that exogenously or endogenously derived ROS can enhance ET-1 production by diabetic rat glomeruli and that ROS scavengers suppress ET- 1 production both in vitro and in vivo. The effects of ROS on ET-1 production of diabetic glomeruli may be partly caused by the effect of hyperglycemia or insulin deficiency.
authors.affiliation: Department of Internal Medicine, Kaohsiung Medical University, Taiwan, ROC.
authors.forename: H C
authors.initials: HC
authors.lastname: Chen
authors.forename: J Y
authors.initials: JY
authors.lastname: Guh
authors.forename: S J
authors.initials: SJ
authors.lastname: Shin
authors.forename: J H
authors.initials: JH
authors.lastname: Tsai
authors.forename: Y H
authors.initials: YH
authors.lastname: Lai
mesh_terms: D000818:Animals; D002374:Catalase / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D019820:Xanthine / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000494:pharmacology
chemical_list: D019332:Endothelin-1; D016166:Free Radical Scavengers; D007328:Insulin; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013481:Superoxides; D019820:Xanthine; D002374:Catalase; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase; D005947:Glucose; D003676:Deferoxamine; D004121:Dimethyl Sulfoxide