ArticleJournal of the American Society of Nephrology : JASN2015
Reduced Renal Methylarginine Metabolism Protects against Progressive Kidney Damage.
Article in Journal of the American Society of Nephrology : JASN, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 34 citations in OpenAlex.
- Lysosome-derived methylated arginine is a signalling metabolite controlling the lipidome.Nature cell biology · 2026Article
- The Non-Traditional Cardiovascular Culprits in Chronic Kidney Disease: Mineral Imbalance and Uremic Toxin Accumulation.International journal of molecular sciences · 2025Review
- Knock-out of the critical nitric oxide synthase regulator DDAH1 in mice impacts amphetamine sensitivity and dopamine metabolism.Journal of neural transmission (Vienna, Austria : 1996) · 2023Article
- Hepatic DDAH1 mitigates hepatic steatosis and insulin resistance in obese mice: Involvement of reduced S100A11 expression.Acta pharmaceutica Sinica. B · 2023Article
- Role of ADMA in the pathogenesis of microvascular complications in type 2 diabetes mellitus.Frontiers in endocrinology · 2023Review
- Divergent Dimethylarginine Dimethylaminohydrolase Isoenzyme Expression in the Central Nervous System.Cellular and molecular neurobiology · 2022Article
- Association of Variability in the DDAH1, DDAH2, AGXT2 and PRMT1 Genes with Circulating ADMA Concentration in Human Whole Blood.Journal of clinical medicine · 2022Article
- Chronic kidney disease mediates cardiac dysfunction associated with increased resident cardiac macrophages.BMC nephrology · 2022Article
- Protein arginine methyltransferase 3 inhibits renal tubulointerstitial fibrosis through asymmetric dimethylarginine.Frontiers in medicine · 2022Article
- Review
- Specific Lowering of Asymmetric Dimethylarginine by Pharmacological Dimethylarginine Dimethylaminohydrolase Improves Endothelial Function, Reduces Blood Pressure and Ischemia-Reperfusion Injury.The Journal of pharmacology and experimental therapeutics · 2021Article
- Renal asymmetric dimethylarginine inhibits fibrosis.FEBS open bio · 2020Article
- Endothelial Dysfunction in Chronic Kidney Disease, from Biology to Clinical Outcomes: A 2020 Update.Journal of clinical medicine · 2020Review
- The Second Life of Methylarginines as Cardiovascular Targets.International journal of molecular sciences · 2019Review
- Article
- Evidence for a protective role for the rs805305 single nucleotide polymorphism of dimethylarginine dimethylaminohydrolase 2 (DDAH2) in septic shock through the regulation of DDAH activity.Critical care (London, England) · 2018Article
- Regulation of fluid reabsorption in rat or mouse proximal renal tubules by asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase 1.American journal of physiology. Renal physiology · 2018Article
- NRF2 prevents hypertension, increased ADMA, microvascular oxidative stress, and dysfunction in mice with two weeks of ANG II infusion.American journal of physiology. Regulatory, integrative and comparative physiology · 2018Article
- Chronic kidney disease-associated cardiovascular disease: scope and limitations of animal models.Cardiovascular endocrinology · 2017Review
- Inhibitors of the Hydrolytic Enzyme Dimethylarginine Dimethylaminohydrolase (DDAH): Discovery, Synthesis and Development.Molecules (Basel, Switzerland) · 2016Review
Corrections and comments
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Authors and funding
16 authors at 6 institutions in 2 countries.
Funding
Abstract
Nitric oxide (NO) production is diminished in many patients with cardiovascular and renal disease. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis, and elevated plasma levels of ADMA are associated with poor outcomes. Dimethylarginine dimethylaminohydrolase-1 (DDAH1) is a methylarginine-metabolizing enzyme that reduces ADMA levels. We reported previously that a DDAH1 gene variant associated with increased renal DDAH1 mRNA transcription and lower plasma ADMA levels, but counterintuitively, a steeper rate of renal function decline. Here, we test the hypothesis that reduced renal-specific ADMA metabolism protects against progressive renal damage. Renal DDAH1 is expressed predominately within the proximal tubule. A novel proximal tubule-specific Ddah1 knockout (Ddah1(PT-/-)) mouse demonstrated tubular cell accumulation of ADMA and lower NO concentrations, but unaltered plasma ADMA concentrations. Ddah1(PT-/-) mice were protected from reduced kidney tissue mass, collagen deposition, and profibrotic cytokine expression in two independent renal injury models: folate nephropathy and unilateral ureteric obstruction. Furthermore, a study of two independent kidney transplant cohorts revealed higher levels of human renal allograft methylarginine-metabolizing enzyme gene expression associated with steeper function decline. We also report an association among DDAH1 expression, NO activity, and uromodulin expression supported by data from both animal and human studies, raising the possibility that kidney DDAH1 expression exacerbates renal injury through uromodulin-related mechanisms. Together, these data demonstrate that reduced renal tubular ADMA metabolism protects against progressive kidney function decline. Thus, circulating ADMA may be an imprecise marker of renal methylarginine metabolism, and therapeutic ADMA reduction may even be deleterious to kidney function.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.