title: Extracellular superoxide dismutase ameliorates streptozotocin-induced rat diabetic nephropathy via inhibiting the ROS/ERK1/2 signaling.
abstract: OBJECTIVE
  Diabetic nephropathy is the leading cause of end stage renal disease in developed countries throughout the world. The imbalance between the production of reactive oxygen species (ROS) and the antioxidant defense system is the main problem that is responsible for the progression of diabetic kidney disease. In this study, we investigated whether human extracellular superoxide dismutase (hEC-SOD) can prevent diabetic nephropathy in the rat model.
  
  
  METHODS
  Diabetic nephropathy symptoms were induced by intraperitoneal injection with 60 mg/kg streptozotocin (STZ) in male Sprague-Dawley (SD) rats. After daily supplement of rhEC-SOD (3200 U/kg/day) for 4 weeks, the serum or urine biochemical markers (glucose, creatinine, blood urea nitrogen, triglyceride, hemoglobin A1c, and microalbuminuria), histological changes, gene expressions (phox47, opn, and gapdh), and protein levels (TGF-β, AT1-R, phospho-p42/p44 MAPK, and p42/p44 MAPK) were determined.
  
  
  RESULTS
  Results showed that rhEC-SOD administration could reverse SOD activity measured in kidney and diabetic-associated changes, including the fibrosis change, expression of collagen I, transforming growth factor-beta (TGF-β) and angiotensin II type I receptor (AT1-R), as well as the activation of the intracellular mitogen-activated protein kinase (MAPK) signaling pathway, associating with its inhibition of p42(MAPK)/p44(MAPK) (ERK1/2) phosphorylation. Additionally, diabetic nephropathy up-regulated the expression of the phox47 and opn genes, and these changes could also be suppressed. Though the proteinuria did not significantly reduce. Treatment with rhEC-SOD ameliorates STZ-induced diabetic nephropathy, leading to reduced death rates, kidney weight/body weight ratio, fibrosis change, and TGF-β1 expression through the down-regulation of ROS/ERK1/2 signaling pathway.
  
  
  CONCLUSIONS
  We conclude that rhEC-SOD can act as a therapeutic agent to protect the progression of diabetic nephropathy.
authors.affiliation: Department of Life Sciences, and Agricultural Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan; Department of Internal Medicine, Taichung Armed Forces General Hospital, Taichung 411, Taiwan; National Defense Medical Center, Taipei 114, Taiwan.
authors.forename: Chia-Wen
authors.initials: CW
authors.lastname: Kuo
authors.affiliation: Department of Life Sciences, and Agricultural Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan.
authors.forename: Chih-Jie
authors.initials: CJ
authors.lastname: Shen
authors.affiliation: Department of Life Sciences, and Agricultural Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan.
authors.forename: Yu-Tang
authors.initials: YT
authors.lastname: Tung
authors.affiliation: Department of Bioresources, Da-Yeh University, Changhwa 515, Taiwan.
authors.forename: Hsiao-Ling
authors.initials: HL
authors.lastname: Chen
authors.affiliation: Department of Life Sciences, and Agricultural Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan.
authors.forename: Yu-Hsuan
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Department of Life Sciences, and Agricultural Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan.
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Chang
authors.affiliation: Department of Life Sciences, and Agricultural Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan.
authors.forename: Kai-Chung
authors.initials: KC
authors.lastname: Cheng
authors.affiliation: Department of Physiology, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Shang-Hsun
authors.initials: SH
authors.lastname: Yang
authors.affiliation: Department of Life Sciences, and Agricultural Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan; Rong Hsing Research Center for Translational Medicine, and the iEGG Center, National Chung Hsing University, Taichung 402, Taiwan. Electronic address: chchen1@dragon.nchu.edu.tw.
authors.forename: Chuan-Mu
authors.initials: CM
authors.lastname: Chen
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000494:pharmacology*
chemical_list: D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; C441642:SOD3 protein, human; D013482:Superoxide Dismutase; D048052:Mitogen-Activated Protein Kinase 3
keywords: Angiotensin II receptor 1; Diabetic nephropathy; Extracellular superoxide dismutase; Mitogen activated protein kinase; Transforming growth factor-beta