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Reduced renal methylarginine metabolism protects against progressive kidney damage

Tomlinson, JAP; Caplin, BD; Boruc, O; Bruce-Cobbold, C; Cutillas, P; Dormann, D; Faull, P; ... Leiper, J; + view all (2015) Reduced renal methylarginine metabolism protects against progressive kidney damage. Journal of the American Society of Nephrology , 26 (12) pp. 3045-3059. 10.1681/ASN.2014030280. Green open access

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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 counter-intuitively, 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 (Ddah1PT-/-) mouse demonstrated tubular cell accumulation of ADMA and lower NO concentrations, but unaltered plasma ADMA concentrations. Ddah1PT-/- 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 associating with steeper function decline. Additionally, we report an association between 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.

Type: Article
Title: Reduced renal methylarginine metabolism protects against progressive kidney damage
Open access status: An open access version is available from UCL Discovery
DOI: 10.1681/ASN.2014030280
Publisher version: http://dx.doi.org/10.1681/ASN.2014030280
Language: English
Additional information: Copyright © 2015 by the American Society of Nephrology.
Keywords: nitric oxide, chronic renal failure, fibrosis, pathophysiology of renal disease and progression, proximal tubule, transgenic mouse
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Renal Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/1465083
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