Toxic Dimethylarginines: Asymmetric  Dimethylarginine (ADMA) and Symmetric  Dimethylarginine (SDMA)

Abstract

Asymmetric and symmetric dimethylarginine (ADMA and SDMA, respectively) are toxic, non-proteinogenic amino acids formed by post-translational modification and are uremic toxins that inhibit nitric oxide (NO) production and play multifunctional roles in many human diseases. Both ADMA and SDMA have emerged as strong predictors of cardiovascular events and death in a range of illnesses. Major progress has been made in research on ADMA-lowering therapies in animal studies; however, further studies are required to fill the translational gap between animal models and clinical trials in order to treat human diseases related to elevated ADMA/SDMA levels. Here, we review the reported impacts of ADMA and SDMA on human health and disease, focusing on the synthesis and metabolism of ADMA and SDMA; the pathophysiological roles of these dimethylarginines; clinical conditions and animal models associated with elevated ADMA and SDMA levels; and potential therapies against ADMA and SDMA. There is currently no specific pharmacological therapy for lowering the levels and counteracting the deleterious effects of ADMA and SDMA. A better understanding of the mechanisms underlying the impact of ADMA and SDMA on a wide range of human diseases is essential to the development of specific therapies against diseases related to ADMA and SDMA.

Transcriptional and Metabolomic Analysis of L-Arginine/Nitric Oxide Pathway in Inflammatory Bowel Disease and Its Association with Local Inflammatory and Angiogenic Response: Preliminary Findings

“…In the currently examined cohort of patients, ADMA was unaltered while arginine and SDMA were decreased in active CD as compared to both controls and active UC. With respect to SDMA, proinflammatory and pro-oxidative in its nature [47], those results are counterintuitive. Nevertheless, they were supported by weak, yet negative, correlation with CDAI.…”

“…DDAH1 is the primary enzyme in ADMA catabolism and there is some uncertainty concerning metabolic activity and the role of DDAH2 [46]. As DDAH enzymes are known mostly as ADMA-metabolizing enzymes and ADMA is primarily implicated in the pathogenesis of cardiovascular diseases [47], little, if not nothing, is known on DDAHs in IBD. Therefore, it would be of interest to address the relevance of presented observations on alterations in PRMT-DDAH interplay in a follow-up study.…”

“…Indeed, upregulated DDAHs correlated with both products of ADMA degradation, that is, citrulline and DMA, which were consistently increased at the systemic level in patients with active and inactive disease. Instead, SDMA is mostly excreted with urine, although its degradation by alanine-glyoxylate aminotransferase 2 (AGXT2) has been shown [47]. An attempt to quantify AGXT2 expression has been made but the enzyme expression in the bowel was too low.…”

Evaluation of Serum Symmetric Dimethylarginine Concentration as a Marker for Masked Chronic Kidney Disease in Cats With Hyperthyroidism

“…In cats, symmetric dimethylarginine (SDMA) has emerged as a potential serum biomarker for early detection of CKD with potential advantages over both urea nitrogen and creatinine . Symmetric dimethylarginine is a byproduct of cellular protein metabolism, specifically the intranuclear methylation of l ‐arginine residues; after proteolysis, these free SDMA residues are then released into the circulation . Symmetric dimethylarginine is not protein‐bound in plasma, is eliminated primarily via renal excretion (>90%), is freely filtered by the glomerulus, and is not secreted or re‐absorbed by the tubules .…”

“…15,16 Symmetric dimethylarginine is a byproduct of cellular protein metabolism, specifically the intranuclear methylation of L-arginine residues; after proteolysis, these free SDMA residues are then released into the circulation. 17 Symmetric dimethylarginine is not protein-bound in plasma, is eliminated primarily via renal excretion (>90%), is freely filtered by the glomerulus, and is not secreted or re-absorbed by the tubules. 16,18 In cats, SDMA concentrations correlate with GFR in an inverse linear relationship, with SDMA increasing as GFR decreases.…”