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. Three groups of uninephrectomized mice were studied: ADMA (60 mg/kg per day), L-NAME (60 mg/kg per day), and isotonic saline (control) were infused through osmotic mini-pumps for 8 weeks. ADMA and L-NAME induced hypertension (PAS 167 ± 16 and 168 ± 10 versus 100 ± 4 mmHg, p < 0.01, respectively). High level of ADMA was associated with increased renal oxidative stress. ADMA treatment induced glomerular and vascular fibrosis as evidenced by the elevated deposits of collagen I, III, and fibronectin (p < 0.01). A similar profile was observed in the L-NAME group. Mice treated with ADMA had reduced peritubular capillaries versus controls (p < 0.01). Collagen I mRNA expression and renal TGF-β1 concentrations were higher in the ADMA and L-NAME groups. Increased level of TGF-β1 was associated with a significant rise of HIF-1α and endothelin-1 expression. These results demonstrate for the first time that elevated concentrations of ADMA are associated with the development of renal fibrosis. These data suggest that in pathophysiological conditions of endothelial dysfunction, the exaggerated endogenous synthesis of ADMA could contribute to CKD progression by favouring hypertension, extracellular matrix synthesis, and rarefaction of peritubular capillaries.

• Authors: Fabrice Mihout, Nasim Shweke, Naïke Bigé, Chantal Jouanneau, Jean-Claude Dussaule, Pierre Ronco, Christos Chatziantoniou, Jean-Jacques Boffa
• Journal: The Journal of pathology (J Pathol) Vol. 223 Issue 1 Pg. 37-45 (Jan 2011) ISSN: 1096-9896 [Electronic] England
• PMID: 20845411 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Chemical References

• Endothelin-1
• Enzyme Inhibitors
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• RNA, Messenger
• Transforming Growth Factor beta1
• N,N-dimethylarginine
• Collagen
• Arginine
• Nitric Oxide Synthase
• NG-Nitroarginine Methyl Ester

Topics

• Animals
• Arginine (analogs & derivatives, blood, toxicity)
• Collagen (biosynthesis, genetics)
• Endothelin-1 (biosynthesis, genetics)
• Enzyme Inhibitors (blood, toxicity)
• Fibrosis
• Gene Expression Regulation (drug effects)
• Hypertension (chemically induced)
• Hypoxia-Inducible Factor 1, alpha Subunit (biosynthesis, genetics)
• Kidney (pathology)
• Male
• Mice
• Mice, Inbred Strains
• NG-Nitroarginine Methyl Ester (toxicity)
• Nitric Oxide Synthase (antagonists & inhibitors)
• Oxidative Stress (drug effects)
• RNA, Messenger (genetics)
• Renal Insufficiency, Chronic (chemically induced, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction (methods)
• Transforming Growth Factor beta1 (biosynthesis, genetics)