title: Proteinuria elevates asymmetric dimethylarginine levels via protein arginine methyltransferase-1 overexpression in a rat model of nephrotic syndrome.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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: Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan. kaida_yuusuke@kurume-u.ac.jp
authors: Yusuke
authors: Y
authors: Kaida
authors: Seiji
authors: S
authors: Ueda
authors: Sho-ichi
authors: S
authors: Yamagishi
authors: Yosuke
authors: Y
authors: Nakayama
authors: Ryotaro
authors: R
authors: Ando
authors: Ryuji
authors: R
authors: Iwatani
authors: Kei
authors: K
authors: Fukami
authors: Seiya
authors: S
authors: Okuda
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000633:toxicity; D004847:Epithelial Cells / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism; D008297:Male; D009404:Nephrotic Syndrome / Q000503:physiopathology*; D018384:Oxidative Stress; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics*; D011507:Proteinuria / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012709:Serum Albumin / Q000008:administration & dosage; D013997:Time Factors
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D012709:Serum Albumin; C018524:N,N-dimethylarginine; D004317:Doxorubicin; D001120:Arginine; D011484:Protein-Arginine N-Methyltransferases; D000111:Acetylcysteine