A functional variant of the dimethylarginine dimethylaminohydrolase-2 gene is associated with chronic kidney disease

Sesti, Giorgio; Mannino, Gaia Chiara; Lorenzo, Carlo De; Greco, Annalisa; Sciacqua, Angela; Marini, Maria Adelaide; Andreozzi, Francesco; Perticone, Francesco

doi:10.1016/j.atherosclerosis.2013.08.041

Cited by 10 publications

(10 citation statements)

References 32 publications

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“…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]. Molecular mechanisms underlying ADMA elevation in CKD include both and increased ADMA production by PRMT and impaired ADMA catabolism by hepatic and renal DDAH, the latter being the predominant factor and a strong predictor of CKD [125]. Several pharmacological agents evaluated in preclinical/Phase IIb studies hold promise to neutralize the deleterious effects of ADMA in NAFLD and CKD, including pentoxifylline [126], quercetin [127], and the FXR agonist obeticholic acid [128], but their impact on clinical endpoints has yet to be assessed.…”

Section: Glomerular Hyperfiltration and Ras Activationmentioning

confidence: 95%

Emerging Liver–Kidney Interactions in Nonalcoholic Fatty Liver Disease

Musso

Cassader

Cohney

et al. 2015

Trends in Molecular Medicine

107

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Section: Glomerular Hyperfiltration and Ras Activationmentioning

confidence: 95%

Emerging Liver–Kidney Interactions in Nonalcoholic Fatty Liver Disease

Musso

Cassader

Cohney

et al. 2015

Trends in Molecular Medicine

107

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“…Interestingly, overexpression of DDAH-1 ameliorated these effects [153]. In human studies, specific genetic polymorphisms of DDAH-1 and DDAH-2 have been associated with chronic kidney disease progression, an effect possibly exerted due to renal micro-vascular damage caused by ADMA accumulation [90,153]. However, the respective DDAH-1 polymorphism was unexpectedly related to decrease ADMA levels [153].…”

Section: Chronic Kidney Diseasementioning

confidence: 98%

Asymmetric Dimethylarginine: Clinical Significance and Novel Therapeutic Approaches

Tousoulis

Georgakis²,

Oikonomou³

et al. 2015

CMC

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Asymmetric dimethylarginine (ADMA) is a competitive endogenous inhibitor of nitric oxide synthase with a key role in the pathophysiology of endothelial dysfunction, in the progression of atherosclerosis and in cardiovascular diseases. Statins, renin-angiotensin-aldosterone system inhibitors, blood glucose lowering agents, insulin sensitizers, beta-blockers, estrogen replacement therapy, antioxidants, complex B vitamins, L-arginine and acetylsalicylic acid have been evaluated for their ability to reduce ADMA levels or inhibit its actions. Despite the major beneficial effects of these agents in cardiovascular disease, research has shown that their favorable actions are only partially mediated by reducing ADMA levels or by bypassing its effect in nitric oxide synthesis. Novel therapeutic approaches targeting selectively ADMA are encouraging, but have only been tested in vitro or in animal studies and further research is needed in order to conclude on how therapeutic strategies modulating ADMA actions can affect atherosclerosis progression and cardiovascular diseases.

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“…In an attempt to clarify this issue, we investigated the association of the rs9267551 polymorphism in the DDAH2 gene with MI in T2DM patients taking advantage of the observation that this polymorphism has a functional impact with the minor C allele exhibiting a higher transcriptional activity resulting in enhanced DDAH2 expression along with higher nitric oxide release in primary human endothelial cells [22]. In addition, the rs9267551 C allele has been associated with lower levels of circulating ADMA, higher insulin sensitivity assessed by euglycemic-hyperinsulinemic clamp studies, and lower risk of renal dysfunction [22,32]. Interestingly, it has been shown that in C2C12 mouse myotubes ADMA is able to induce insulin resistance by reducing expression of both the insulin receptor substrate-1 and GLUT-4 glucose transporter, and increasing expression protein tyrosine phosphatase 1B (PTP1B), thus resulting in impaired insulin signaling, and reduced glucose uptake [33].…”

Section: State Of the Artmentioning

confidence: 99%

A functional variant of the dimethylarginine dimethylaminohydrolase-2 gene is associated with myocardial infarction in type 2 diabetic patients

Mannino

Pezzilli

Averta

et al. 2019

Cardiovasc Diabetol

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Background: Myocardial infarction is the main mortality cause in patients with type 2 diabetes (T2DM). Endothelial dysfunction due to reduced bioavailability of nitric oxide (NO) is an early step of atherogenesis. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis, and it is metabolized by the enzymes dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2. The functional variant rs9267551 C, in the promoter region of DDAH2, has been linked to increased DDAH2 expression, and lower ADMA plasma levels, and was associated with lower risk of coronary artery disease in large-scale genome-wide association studies (GWAS) performed in the general population. However, it is unknown whether this association holds true in T2DM patients. To address this issue, we investigated whether rs9267551 is associated with risk of myocardial infarction in two cohorts of T2DM patients.Methods: SNP rs9267551 was genotyped in 1839 White T2DM patients from the Catanzaro Study (CZ, n = 1060) and the Gargano Heart Study-cross sectional design (GHS, n = 779). Cases were patients with a previous myocardial infarction, controls were asymptomatic patients with neither previous myocardial ischemia nor signs of it at resting and during a maximal symptom limited stress electrocardiogram.Results: Carriers of allele rs9267551 C showed a dose dependent reduction in the risk of myocardial infarction [(CZ = OR 0.380, 95% CI 0.175-0.823, p = 0.014), (GHS = 0.497, 0.267-0.923, p = 0.027), (Pooled = 0.458, 0.283-0.739, p = 0.001)] which remained significant after adjusting for sex, age, BMI, smoking, HbA1c, total cholesterol HDL, and triglyceride levels [(CZ = 0.307, 0.106-0.885, p = 0.029), (GHS = 0.512, 0.270-0.970, p = 0.040), (Pooled = 0.458, 0.266-0.787, p = 0.005)]. Conclusions:We found that rs9267551 polymorphism is significantly associated with myocardial infarction in T2DM patients of European ancestry from two independent cohorts. It is possible that in subjects carrying the protective C allele less ADMA accumulates in endothelial cells causing vascular protection as a consequence of higher nitric oxide availability.

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A functional variant of the dimethylarginine dimethylaminohydrolase-2 gene is associated with chronic kidney disease

Cited by 10 publications

References 32 publications

Emerging Liver–Kidney Interactions in Nonalcoholic Fatty Liver Disease

Emerging Liver–Kidney Interactions in Nonalcoholic Fatty Liver Disease

Asymmetric Dimethylarginine: Clinical Significance and Novel Therapeutic Approaches

A functional variant of the dimethylarginine dimethylaminohydrolase-2 gene is associated with myocardial infarction in type 2 diabetic patients

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