title: Reduced Renal Methylarginine Metabolism Protects against Progressive Kidney Damage.
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.
authors: Medical Research Council Clinical Sciences Centre, Imperial College, London, United Kingdom; j.tomlinson@imperial.ac.uk.
authors: James A P
authors: JA
authors: Tomlinson
authors: Centre for Nephrology, UCL Medical School Royal Free, London, United Kingdom;
authors: Ben
authors: B
authors: Caplin
authors: Medical Research Council Clinical Sciences Centre, Imperial College, London, United Kingdom;
authors: Olga
authors: O
authors: Boruc
authors: Medical Research Council Clinical Sciences Centre, Imperial College, London, United Kingdom;
authors: Claire
authors: C
authors: Bruce-Cobbold
authors: Medical Research Council Clinical Sciences Centre, Imperial College, London, United Kingdom;
authors: Pedro
authors: P
authors: Cutillas
authors: Medical Research Council Clinical Sciences Centre, Imperial College, London, United Kingdom;
authors: Dirk
authors: D
authors: Dormann
authors: Medical Research Council Clinical Sciences Centre, Imperial College, London, United Kingdom;
authors: Peter
authors: P
authors: Faull
authors: Centre for Nephrology, UCL Medical School Royal Free, London, United Kingdom;
authors: Rebecca C
authors: RC
authors: Grossman
authors: Medical Research Council Clinical Sciences Centre, Imperial College, London, United Kingdom;
authors: Sanjay
authors: S
authors: Khadayate
authors: Translational Genomics Transplant Laboratory, Transplant Division, Department of Surgery, University of Virginia, Charlottesville, Virginia;
authors: Valeria R
authors: VR
authors: Mas
authors: Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom; and.
authors: Dorothea D
authors: DD
authors: Nitsch
authors: Medical Research Council Clinical Sciences Centre, Imperial College, London, United Kingdom;
authors: Zhen
authors: Z
authors: Wang
authors: Centre for Nephrology, UCL Medical School Royal Free, London, United Kingdom;
authors: Jill T
authors: JT
authors: Norman
authors: Hypertension, Kidney and Vascular Research Center, Georgetown University, Washington, DC.
authors: Christopher S
authors: CS
authors: Wilcox
authors: Centre for Nephrology, UCL Medical School Royal Free, London, United Kingdom;
authors: David C
authors: DC
authors: Wheeler
authors: Medical Research Council Clinical Sciences Centre, Imperial College, London, United Kingdom;
authors: James
authors: J
authors: Leiper
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D064591:Allografts / Q000378:metabolism; D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism; D024042:Collagen Type I / Q000652:urine; D000090602:Collagen Type I, alpha 1 Chain; D005260:Female; D005492:Folic Acid / Q000009:adverse effects; D015870:Gene Expression; D005919:Glomerular Filtration Rate; D006801:Humans; D016030:Kidney Transplantation; D007687:Kidney Tubules, Proximal / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000637:Transaminases / Q000235:genetics / Q000378:metabolism; D014517:Ureteral Obstruction / Q000150:complications; D058949:Uromodulin / Q000652:urine
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D012333:RNA, Messenger; D058949:Uromodulin; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D005492:Folic Acid; D001120:Arginine; D000637:Transaminases; C019635:Alanine-glyoxylate transaminase; D000581:Amidohydrolases; C059999:dimethylargininase
keywords: chronic renal failure; fibrosis; nitric oxide; pathophysiology of renal disease and progression; proximal tubule; transgenic mouse