2010
DOI: 10.1002/path.2769
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Asymmetric dimethylarginine (ADMA) induces chronic kidney disease through a mechanism involving collagen and TGF‐β1 synthesis

Abstract: Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, is accumulated in plasma during chronic kidney disease (CKD). It is considered an independent mortality and cardiovascular risk factor in CKD patients. To test the involvement of ADMA in CKD progression, we investigated the effects of chronic ADMA administration on renal structure and compared these effects with NG-nitro-L-arginine methyl ester (L-NAME) treatment, a widely used exogenous inhibitor of NOS that induces CKD. … Show more

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Cited by 94 publications
(90 citation statements)
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References 39 publications
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“…Because high FGF-23-Klotho almost completely suppresses NO synthase, 35,36 ADMA at high FGF-23 levels has no effect on the risk of CKD progression, an outcome strongly influenced by the NO system. 24 The observation that in the MMKD cohort not only ADMA but also SDMA (i.e., a methylarginine that inhibits NO synthesis by reducing cellular L-arginine uptake) showed a competitive interaction with c-terminal FGF-23 adds circumstantial support to our interpretation that these interactions depend on the interference of FGF-23-Klotho with the NO system. Of note, the interaction between FGF-23 and ADMA was specific for the risk of renal events because no such interaction emerged for cardiovascular events and death in the Southern Italy cohort, emphasizing the peculiar sensitivity of the kidney to disturbances impinging upon the NO system.…”
Section: Discussionsupporting
confidence: 52%
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“…Because high FGF-23-Klotho almost completely suppresses NO synthase, 35,36 ADMA at high FGF-23 levels has no effect on the risk of CKD progression, an outcome strongly influenced by the NO system. 24 The observation that in the MMKD cohort not only ADMA but also SDMA (i.e., a methylarginine that inhibits NO synthesis by reducing cellular L-arginine uptake) showed a competitive interaction with c-terminal FGF-23 adds circumstantial support to our interpretation that these interactions depend on the interference of FGF-23-Klotho with the NO system. Of note, the interaction between FGF-23 and ADMA was specific for the risk of renal events because no such interaction emerged for cardiovascular events and death in the Southern Italy cohort, emphasizing the peculiar sensitivity of the kidney to disturbances impinging upon the NO system.…”
Section: Discussionsupporting
confidence: 52%
“…20 NO inhibition has profound effects on kidney function, including impaired ability to dispose of a sodium load, decrease in renal blood flow, and increase in filtration fraction 32 and TGF-b-mediated renal fibrosis. 24 The nitric oxide system is fundamental for vasoregulation. In previous studies in patients with CKD we found that high ADMA and high FGF-23 were associated with altered endothelium-dependent response to forearm ischemia.…”
Section: Discussionmentioning
confidence: 99%
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“…21 Previously published rodent studies of kidney fibrosis have reported that DDAH1 and NO are protective while ADMA is pathogenic; however, significant study design issues limit their interpretation. ADMA or L-NAME infusion into mice exacerbated renal fibrosis, but both raised SBP by approximately 60 mmHg, suggesting hypertensive injury 28 ; global DDAH1 overexpression, however, protected against fibrosis in angiotensin and surgical nephron-reduction models of CKD. 29,30 Genetic DDAH1 overexpression decreases circulating ADMA and introduces unmeasured effects upon normal regulatory mechanisms.…”
Section: Discussionmentioning
confidence: 99%
“…These findings indicate that TGF-b is a very important inducer of PRMT1 in inflammation. Although there is no direct evidence to prove the relationship between TGF-b and PRMT1, a study on renal fibrosis was found that ADMA, as an endogenous endothelial NO synthase and inducible NO synthase competitive inhibitor (17,18), can reduce the NO concentration in serum in asthmatic animals (7); furthermore, ADMA is also involved in proline metabolism, which may play an important role in the pulmonary remodeling process through raising collagen synthesis (19). In our study, the supplementation of TGF-b to basic medium increased the expression of PRMT1 in fibroblasts.…”
Section: Discussionmentioning
confidence: 99%