Kidney and liver are the main organs of expression of a key metabolic enzyme alanine:glyoxylate aminotransferase 2 in humans

Jarzebska, Natalia; Georgi, Sophia; Jabs, Normund; Brilloff, Silke; Maas, Renke; Rodionov, Roman N.; Zietz, Christian; Montresor, Sabrina; Hohenstein, Bernd; Weiss, Norbert

doi:10.1016/j.atherosclerosissup.2019.08.041

Cited by 13 publications

(8 citation statements)

References 28 publications

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“…It is interesting to note, however, that the previously described correlation of ADMA with renal function was reproduced in this study by showing a significant association of ADMA tertiles with serum creatinine concentration [39,40]. DDAH1 is highly expressed in renal tissue, as is AGXT2; the correlation of ADMA with creatinine may therefore point to dysregulation of the expression and/or activity of these ADMA-metabolizing enzymes in the kidneys rather than to reduced excretion of unchanged ADMA into the urine [41,42]. Elevated ADMA concentration in kidney disease may thus explain the high incidence of cardiovascular co-morbidity in this patient population.…”

Section: Discussionsupporting

confidence: 66%

Association of Variability in the DDAH1, DDAH2, AGXT2 and PRMT1 Genes with Circulating ADMA Concentration in Human Whole Blood

Hannemann

Zummack

Hillig

et al. 2022

JCM

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Asymmetric dimethylarginine is an endogenous inhibitor of nitric oxide synthesis and a cardiovascular risk factor. Its regulation has been studied extensively in experimental models, but less in humans. We studied common single-nucleotide polymorphisms (SNPs) in genes encoding for enzymes involved in ADMA biosynthesis and metabolism, i.e., PRMT1, DDAH1, DDAH2, and AGXT2, and assessed their associations with blood ADMA concentration in 377 unselected humans. The minor allele of DDAH1 SNP rs233112 was significantly more frequent in individuals with ADMA in the highest tertile or in the highest quartile, as was the major allele of DDAH2 rs805304. A combined genotype comprising both SNPs showed a significant genotype–phenotype association, with increasing ADMA concentration by an increasing number of inactive alleles. SNPs in the AGXT2 and PRMT1 genes showed no significant associations with blood ADMA concentration. Our study provides comprehensive evidence that DDAH1 and DDAH2 are the major enzymes regulating blood ADMA concentration, whilst PRMT1 indirectly affects ADMA, and AGXT2 may act as a back-up enzyme in ADMA metabolism under pathophysiological conditions only.

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Section: Discussionsupporting

confidence: 66%

Association of Variability in the DDAH1, DDAH2, AGXT2 and PRMT1 Genes with Circulating ADMA Concentration in Human Whole Blood

Hannemann

Zummack

Hillig

et al. 2022

JCM

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“…hArg is extensively metabolized in the liver, kidney and other organs 1 . Catabolism of hArg is catalyzed by AGAT and degradation of hArg is catalyzed by AGXT2 35 . Moreover, hArg is a substrate and competitive inhibitor of arginases 1 .…”

Section: Discussionmentioning

confidence: 99%

The relationship between homoarginine and liver biomarkers: a combination of epidemiological and clinical studies

Aghdassi

Schwedhelm

Atzler

et al. 2023

Sci Rep

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Homoarginine (hArg) is a non-essential cationic amino acid which inhibits hepatic alkaline phosphatases to exert inhibitory effects on bile secretion by targeting intrahepatic biliary epithelium. We analyzed (1) the relationship between hArg and liver biomarkers in two large population-based studies and (2) the impact of hArg supplementation on liver biomarkers. We assessed the relationship between alanine transaminase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), alkaline phosphatases (AP), albumin, total bilirubin, cholinesterase, Quick’s value, liver fat, and Model for End-stage Liver Disease (MELD) and hArg in appropriately adjusted linear regression models. We analyzed the effect of L-hArg supplemention (125 mg L-hArg daily for 4 weeks) on these liver biomarkers. We included 7638 individuals (men: 3705; premenopausal women: 1866, postmenopausal women: 2067). We found positive associations for hArg and ALT (β 0.38 µkatal/L 95% confidence interval (CI): 0.29; 0.48), AST (β 0.29 µkatal/L 95% CI 0.17; 0.41), GGT (β 0.033 µkatal/L 95% CI 0.014; 0.053), Fib-4 score (β 0.08 95% CI 0.03; 0.13), liver fat content (β 0.016% 95% CI 0.006; 0.026), albumin (β 0.030 g/L 95% CI 0.019; 0.040), and cholinesterase (β 0.003 µkatal/L 95% CI 0.002; 0.004) in males. In premenopausal women hArg was positively related with liver fat content (β 0.047% 95%CI 0.013; 0.080) and inversely with albumin (β − 0.057 g/L 95% CI − 0.073; − 0.041). In postmenopausal women hARG was positively associated with AST (β 0.26 µkatal/L 95% CI 0.11; 0.42). hArg supplementation did not affect liver biomarkers. We summarize that hArg may be a marker of liver dysfunction and should be explored further.

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“…The Western Blot analysis was performed as described in Ref. 29 . Membranes were stained by Ponceau reagent (Sigma-Aldrich, St. Louis, MI, USA) to control for the protein transfer and then blocked in 5% milk for 1 h at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

Overexpression of alanine-glyoxylate aminotransferase 2 protects from asymmetric dimethylarginine-induced endothelial dysfunction and aortic remodeling

Rodionov

Jarzebska

Burdin

et al. 2022

Sci Rep

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Elevated plasma concentrations of asymmetric dimethylarginine (ADMA) are associated with an increased risk of mortality and adverse cardiovascular outcomes. ADMA can be metabolized by dimethylarginine dimethylaminohydrolases (DDAHs) and by alanine-glyoxylate aminotransferase 2 (AGXT2). Deletion of DDAH1 in mice leads to elevation of ADMA in plasma and increase in blood pressure, while overexpression of human DDAH1 is associated with a lower plasma ADMA concentration and protective cardiovascular effects. The possible role of alternative metabolism of ADMA by AGXT2 remains to be elucidated. The goal of the current study was to test the hypothesis that transgenic overexpression of AGXT2 leads to lowering of plasma levels of ADMA and protection from vascular damage in the setting of DDAH1 deficiency. We generated transgenic mice (TG) with ubiquitous overexpression of AGXT2. qPCR and Western Blot confirmed the expression of the transgene. Systemic ADMA levels were decreased by 15% in TG mice. In comparison with wild type animals plasma levels of asymmetric dimethylguanidino valeric acid (ADGV), the AGXT2 associated metabolite of ADMA, were six times higher. We crossed AGXT2 TG mice with DDAH1 knockout mice and observed that upregulation of AGXT2 lowers plasma ADMA and pulse pressure and protects the mice from endothelial dysfunction and adverse aortic remodeling. Upregulation of AGXT2 led to lowering of ADMA levels and protection from ADMA-induced vascular damage in the setting of DDAH1 deficiency. This is especially important, because all the efforts to develop pharmacological ADMA-lowering interventions by means of upregulation of DDAHs have been unsuccessful.

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Kidney and liver are the main organs of expression of a key metabolic enzyme alanine:glyoxylate aminotransferase 2 in humans

Cited by 13 publications

References 28 publications

Association of Variability in the DDAH1, DDAH2, AGXT2 and PRMT1 Genes with Circulating ADMA Concentration in Human Whole Blood

Association of Variability in the DDAH1, DDAH2, AGXT2 and PRMT1 Genes with Circulating ADMA Concentration in Human Whole Blood

The relationship between homoarginine and liver biomarkers: a combination of epidemiological and clinical studies

Overexpression of alanine-glyoxylate aminotransferase 2 protects from asymmetric dimethylarginine-induced endothelial dysfunction and aortic remodeling

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