Proteinuria elevates asymmetric dimethylarginine levels via protein arginine methyltransferase-1 overexpression in a rat model of nephrotic syndrome.

Abstract

AIMS:

Proteinuria is an independent risk factor for cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Asymmetric dimethylarginine (ADMA) is a mediator of endothelial dysfunction and is associated with proteinuria in CKD patients. Thus, ADMA can partially account for the increased risk of CVD in CKD patients presenting proteinuria. However, a causal relationship between proteinuria and ADMA remains to be demonstrated.

MAIN METHODS:

We first investigated whether and how proteinuria might increase ADMA levels in adriamycin (ADR)-treated rats. Next, we examined the effects of human serum albumin (HSA) on ADMA production by human renal proximal tubular epithelial cells (RPTECs) cultured in vitro.

KEY FINDINGS:

Proteinuria was associated with ADMA levels in ADR treated rats. Although ADR treatment did not affect the expression levels of the dimethylarginine dimethylaminohydrolase (DDAH)-1 or -2 enzymes that degrade ADMA, it significantly increased the expression levels of protein arginine methyltransferase-1 (PRMT-1) that facilitates the production of ADMA. HSA increased the generation of reactive oxygen species in RPTECs, which was blocked by the anti-oxidant N-acetylcysteine (NAC) or an inhibitor of NADPH oxidase. Furthermore, HSA increased ADMA generation by RPTECs in a dose- and time-dependent manner and induced gene expression of PRMT-1 but not DDAHs, which were also suppressed by NAC.

SIGNIFICANCE:

Our data suggest that proteinuria might enhance ADMA generation in tubular cells, at least in part via the overexpression of PRMT-1 triggered by oxidative stress. Our findings thereby propose a mechanistic link between proteinuria and ADMA levels in CKD patients.

• Authors: Yusuke Kaida, Seiji Ueda, Sho-ichi Yamagishi, Yosuke Nakayama, Ryotaro Ando, Ryuji Iwatani, Kei Fukami, Seiya Okuda
• Journal: Life sciences (Life Sci) Vol. 91 Issue 9-10 Pg. 301-5 (Sep 24 2012) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 22749861 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Antioxidants
• Reactive Oxygen Species
• Serum Albumin
• N,N-dimethylarginine
• Doxorubicin
• Arginine
• Protein-Arginine N-Methyltransferases
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Animals
• Antioxidants (pharmacology)
• Arginine (analogs & derivatives, metabolism)
• Cells, Cultured
• Disease Models, Animal
• Doxorubicin (toxicity)
• Epithelial Cells (metabolism)
• Gene Expression Regulation, Enzymologic
• Humans
• Kidney Tubules, Proximal (cytology, metabolism)
• Male
• Nephrotic Syndrome (physiopathology)
• Oxidative Stress
• Protein-Arginine N-Methyltransferases (genetics)
• Proteinuria (physiopathology)
• Rats
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)
• Serum Albumin (administration & dosage)
• Time Factors