Involvement of Increased Endogenous Asymmetric Dimethylarginine in the Hepatic Endoplasmic Reticulum Stress of Type 2 Diabetic RatsReportar como inadecuado

Involvement of Increased Endogenous Asymmetric Dimethylarginine in the Hepatic Endoplasmic Reticulum Stress of Type 2 Diabetic Rats - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.


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.


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.


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.


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.

Autor: Yi-Ping Leng, Ni Qiu, Wei-jin Fang, Mei Zhang, Zhi-Min He, Yan Xiong



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