Alanine-Glyoxylate Aminotransferase-2 Metabolizes Endogenous Methylarginines, Regulates NO, and Controls Blood Pressure

Abstract

Objective-Asymmetric dimethylarginine is an endogenous inhibitor of NO synthesis that may mediate cardiovascular disease. Alanine-glyoxylate aminotransferase-2 (AGXT2) has been proposed to degrade asymmetric dimethylarginine. We investigated the significance of AGXT2 in methylarginine metabolism in vivo and examined the effect of this enzyme on blood pressure. Methods and Results-In isolated mouse kidney mitochondria, we show asymmetric dimethylarginine deamination under physiological conditions. We demonstrate increased asymmetric dimethylarginine, reduced NO, and hypertension in an AGXT2 knockout mouse. We provide evidence for a role of AGXT2 in methylarginine metabolism in humans by demonstrating an inverse relationship between renal (allograft) gene expression and circulating substrate levels and an association between expression and urinary concentrations of the product. Finally, we examined data from a meta-analysis of blood pressure genome-wide association studies. No genome-wide significance was observed, but taking a hypothesisdriven approach, there was a suggestive association between the T allele at rs37369 (which causes a valine-isoleucine substitution and altered levels of AGXT2 substrate) and a modest increase in diastolic blood pressure (P=0.0052). Conclusion-Although the effect of variation at rs37369 needs further study, these findings suggest that AGXT2 is an important regulator of methylarginines and represents a novel mechanism through which the kidney regulates blood pressure. (Arterioscler Thromb Vasc Biol. 2012;32:2892-2900.)Key Words: alanine-glyoxylate aminotransferase-2 ◼ asymmetric dimethylarginine ◼ hypertension ◼ kidney ◼ NO

Asymmetric and Symmetric Dimethylarginine and Sympathetic Nerve Traffic after Renal Denervation in Patients with Resistant Hypertension

“…ADMA and SDMA are also metabolized by an alternative pathway by alanine-glyoxylate aminotransferase 2, a mitochondrial aminotransferase expressed primarily in the kidney. The plasma concentration of these methylarginines in renal transplant patients correlates inversely with the renal expression of alanine-glyoxylate aminotransferase 2 (26). ADMA is substantially raised in hyperthyroidism (27) and critical illness (28), that is, two conditions characterized by high sympathetic activity (29,30) and enhanced protein degradation (31,32), suggesting that reduced sympathetic activity after renal denervation may attenuate the release of these compounds from methylated proteins.…”

Reduced Renal Methylarginine Metabolism Protects against Progressive Kidney Damage

“…(AGXT2) 5 -metabolize ADMA and other methylarginines to inactive products. Thus, MAMEs represent alternative pathways of endogenous NO regulation.…”

“…Thus, MAMEs represent alternative pathways of endogenous NO regulation. 6 The kidney expresses all MAME and NOS isoforms in a cellspecific distribution, 5,7,8 thereby providing the means for intricate, cell type-specific control of NO bioavailability. Renal NO regulates hemodynamics, 9 afferent arteriolar vascular reactivity, 10 glomerular filtration, 11 tubular reabsorption, and solute excretion.…”

Asymmetric and symmetric dimethylarginine as risk markers for total mortality and cardiovascular outcomes: A systematic review and meta-analysis of prospective studies

“…The plasma levels of ADMA and SDMA are affected by several overlapping as well as distinct metabolic pathways. [3,4,[85][86][87][88][89][90] Elevation of ADMA may predominantly represent impaired dimethylarginine dimethylaminohydrolase (DDAH) activity [4] while elevation of SDMA more likely reflects impaired renal function [91,92] and/or impaired alanine-glyoxylate aminotransferase 2 (AGXT2) activity (i.e. hyper beta-aminoisobutyric acid uria).…”