title: Involvement of increased endogenous asymmetric dimethylarginine in the hepatic endoplasmic reticulum stress of type 2 diabetic rats.
abstract: OBJECTIVE
  Increasing evidence suggested that endoplasmic reticulum (ER) stress contributes to insulin resistance, which plays an important role in the development of type 2 diabetes mellitus (T2DM). Accumulation of endogenous nitric oxide synthase (NOS) inhibitor, asymmetric dimethylarginine (ADMA), is associated with insulin resistance, T2DM, and diabetic cardiovascular complications, although the mechanisms have not been elucidated. This study was to determine whether elevated endogenous ADMA is involved in hepatic ER stress of type 2 diabetic rats, verify their causal relationship, and elucidate the potential mechanism underlying ADMA induced ER stress in rat hepatocytes.
  
  
  METHODS
  Immunoglobulin binding protein (Bip) transcription, eukaryotic initiation factor 2α kinase (eIF2α) phosphorylation, X box-binding protein-1 (XBP-1) mRNA splicing and C/EBP homologues protein (CHOP) expression were measured to reflect ER stress. Contents of ADMA and nitrite/nitrate as well as activities or expression of NOS and dimethylarginine dimethylaminohydrolase (DDAH) were detected to show the changes in DDAH/ADMA/NOS/NO pathway. The lipid peroxidation product malondialdehyde content and antioxidant enzyme superoxide dismutase activity were analyzed to evaluate oxidative stress.
  
  
  RESULTS
  ER stress was provoked in the liver of type 2 diabetic rats, as expressed by increases of Bip transcription, eIF2α phosphorylation, XBP-1 splicing and CHOP expression, all of which were in parallel with the elevation of serum ADMA, suppression of NO generation, NOS and DDAH activities in the liver. Exposure of hepatocytes to ADMA or hydrogen peroxide also induced ER stress, which was associated with the inhibition of NO production and increase of oxidative stress. Treatment of hepatocytes with antioxidant pyrrolidine dithiocarbamate not only decreased ADMA-induced oxidative stress and inhibition of NO production but also reduced ADMA-triggered ER stress.
  
  
  CONCLUSIONS
  These results indicate that increased endogenous ADMA contributes to hepatic ER stress in type 2 diabetic rats, and the mechanism underlying ADMA-induced ER stress may relate to oxidative stress via NOS uncoupling.
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, P.R. China.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Leng
authors.affiliation: Department of Pharmacology, Guangzhou Research Institute of Snake Venom and School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, P.R. China.
authors.forename: Ni
authors.initials: N
authors.lastname: Qiu
authors.affiliation: Department of Pharmacology, Guangzhou Research Institute of Snake Venom and School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, P.R. China.
authors.forename: Wei-jin
authors.initials: WJ
authors.lastname: Fang
authors.affiliation: Department of Pharmacology, Guangzhou Research Institute of Snake Venom and School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, P.R. China.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Cancer Research Institute and Cancer Hospital, Guangzhou Medical University, Guangzhou, Guangdong, P.R. China.
authors.forename: Zhi-Min
authors.initials: ZM
authors.lastname: He
authors.affiliation: Department of Pharmacology, Guangzhou Research Institute of Snake Venom and School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, P.R. China; Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiong
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D008099:Liver / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase