• DDAH2
• EPO resistance
• asymmetric dimethylarginine
• genetic polymorphism
• oxidative stress

• Alleles
• Amidohydrolases/genetics
• Arginine/analogs & derivatives
• Arginine/blood
• Asian People/genetics
• Erythropoietin/blood
• Female
• Genotype
• Humans
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Renal Dialysis

Asymmetric-dimethylarginine (ADMA) competes with L-arginine for each of the three isoforms of nitric oxide synthase: endothelial; neuronal; inducible. ADMA is synthesized by protein methyltransferases followed by proteolytic degradation. ADMA is metabolized to citrulline and dimethylamine, by dimethylarginine dimethylaminohydrolase (DDAH) and enters cells through cationic amino-acid transporters extensively expressed in the liver. The liver plays a crucial role in ADMA metabolism by DDAH-1 and, as has been recently demonstrated, it is also responsible for ADMA biliary excretion. A correlation has been demonstrated between plasma ADMA levels and the degree of hepatic dysfunction in patients suffering from liver diseases with varying aetiologies: plasma ADMA levels are increased in patients with liver cirrhosis, alcoholic hepatitis and acute liver failure. The mechanism by which liver dysfunction results in raised ADMA concentrations is probably due to impaired activity of DDAH due to severe inflammation, oxidative stress, and direct damage to DDAH. High plasma ADMA levels are also relevant as they are associated with the onset of multi-organ failure (MOF). Increased plasma concentration of ADMA was identified as an independent risk factor for MOF in critically-ill patients causing enhanced Intensive Care Unit mortality: a significant reduction in nitric oxide synthesis, leading to malperfusion in various organs, eventually culminating in multi organs dysfunction.

• Liver
• Asymmetric dimethylarginine
• Nitric oxide
• Nitric oxide-synthase
• Multiple organ failure

• Animals
• Arginine/analogs & derivatives
• Arginine/blood
• Arginine/metabolism
• Biomarkers/blood
• Critical Illness
• Humans
• Liver/metabolism
• Liver/pathology
• Liver Diseases/blood
• Liver Diseases/etiology
• Liver Diseases/metabolism
• Liver Diseases/pathology
• Liver Diseases/therapy
• Multiple Organ Failure/etiology
• Multiple Organ Failure/metabolism
• Prognosis
• Risk Factors
• Signal Transduction
• Up-Regulation

• Chronic renal failure
• Exercise
• Sympathetic nerve activity

We investigated the effects of hepatic ischemia/reperfusion (I/R) injury on asymmetric dimethylarginine (ADMA, a nitric oxide synthase inhibitor), protein methyltransferase (PRMT) and dimethylarginine dimethylaminohydrolase (DDAH) (involved, resp., in ADMA synthesis and degradation), and the cationic transporter (CAT). Male Wistar rats were subjected to 30 or 60 min hepatic ischemia followed by 60 min reperfusion. ADMA levels in serum and bile were determined. Tissue ADMA, DDAH activity, DDAH-1 and CAT-2 protein, DDAH-1 and PRMT-1 mRNA expression, GSH/GSSG, ROS production, and lipid peroxidation were detected. ADMA was found in bile. I/R increased serum and bile ADMA levels while an intracellular decrease was detected after 60 min ischemia. Decreased DDAH activity, mRNA, and protein expression were observed at the end of reperfusion. No significant difference was observed in GSH/GSSG, ROS, lipid peroxidation, and CAT-2; a decrease in PRMT-1 mRNA expression was found after I/R. Liver is responsible for the biliary excretion of ADMA, as documented here for the first time, and I/R injury is associated with an oxidative stress-independent alteration in DDAH activity. These data are a step forward in the understanding of the pathways that regulate serum, tissue, and biliary levels of ADMA in which DDAH enzyme plays a crucial role.

Patients with chronic kidney disease are at significantly increased risk for cardiovascular disease and sudden cardiac death. One mechanism underlying increased cardiovascular risk in patients with renal failure includes overactivation of the sympathetic nervous system (SNS). Multiple human and animal studies have shown that central sympathetic outflow is chronically elevated in patients with both end-stage renal disease (ESRD) and chronic kidney disease (CKD). SNS overactivation, in turn, increases the risk of cardiovascular disease and sudden death by increasing arterial blood pressure, arrythmogenicity, left ventricular hypertrophy, and coronary vasoconstriction and contributes to the progression renal disease. This paper will examine the evidence for SNS overactivation in renal failure from both human and experimental studies and discuss mechanisms of SNS overactivity in CKD and therapeutic implications.