Involvement of Increased Endogenous Asymmetric Dimethylarginine in the Hepatic Endoplasmic Reticulum Stress of Type 2 Diabetic Rats

Abstract

ObjectiveIncreasing 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.MethodsImmunoglobulin 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.ResultsER 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.ConclusionsThese 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.

Resveratrol Ameliorates the Components of Hepatic Inflammation and Apoptosis in a Rat Model of Streptozotocin‐Induced Diabetes

“…ADMA, an endogenous inhibitor of NOS synthesis from L‐Arginine inhibits cellular uptake of L‐Arginine by suppressing the NOS activity. Hepatic ADMA levels are increased in diabetic rats [Leng et al, ] which are confirmed in this study, an effect that is reversed by resveratrol treatment. These results suggest that increased iNOS levels due to diabetes‐induced inflammation, results in a positive‐feedback on ADMA content.…”

MCD diet-induced steatohepatitis is associated with alterations in asymmetric dimethylarginine (ADMA) and its transporters

“…Rats fed with a choline and methionine were used as controls. The results are reported as the mean ± SE of 5 animals for MCD group and n = 3 for control group the case with diabetic rats, where an increase in serum levels of glucose, cholesterol and triglyceride has been found and where high ADMA levels have been detected [27].…”

Emerging Liver–Kidney Interactions in Nonalcoholic Fatty Liver Disease

“…Ammonia and Uremic toxins absorption by AST-120 [115] Asymmetric dimethylarginine (ADMA) Cellular mechanism [121,122] Biological effect Therapeutic implications…”

“…ADMA is an endogenous inhibitor of NO synthase and can induce endothelial dysfunction, insulin resistance, ER stress, and TGF-b production in hepatocytes and glomerulo-tubular endothelial cells, promoting hepatic and kidney injury and fibrosis [121,122]. Accordingly, plasma ADMA levels are increased in patients with NAFLD and/or with CKD, correlate with renal dysfunction, and predict CKD progression, early atherosclerosis, and CVD events in these patient populations [123,124].…”