title: Effects of losartan and pentoxifylline on renal dimethylarginine dimethylaminohydrolase-1 expression in proteinuric nephropathy.
abstract: OBJECTIVE
  Circulatory asymmetric dimethylarginine (ADMA) is correlated with proteinuria and endothelial dysfunction in patients with proteinuric renal diseases. However, it is not known whether proteinuria itself affects expression of dimethylarginine dimethylaminohydrolase (DDAH), a degrading enzyme of ADMA, in kidney. The aim of this study is to evaluate the direct effects of losartan and/or pentoxifylline on expression of renal DDAH-1 and its relation to oxidative stress in the setting of albuminuria.
  
  
  METHODS
  Using NRK52E cells, DDAH-1 mRNA and protein were determined after exposure to albumin with losartan and/or pentoxifylline. Reactive oxygen species (ROS), PKC activity, and NOX-4 mRNA were also measured. In addition, the effect of losartan and/or pentoxifylline on renal expression of DDAH-1 and serum ADMA were evaluated in a rat model of proteinuric nephropathy.
  
  
  RESULTS
  Exposure to albumin resulted in increased release of N-acetyl-β-D-glucosaminidase along with an increase of TNF-α, 8-hydroxy-2'-deoxyguanosine, and angiotensin II in NRK52E cells. Losartan and pentoxifylline reversed albumin-induced decrease of DDAH-1 mRNA and protein expression and DDAH-1 activity. The effects of losartan and pentoxifylline on DDAH-1 mRNA were associated with reduction of ROS. In addition, treatment with losartan and pentoxifylline resulted in an attenuated change of renal DDAH-1 protein expression and serum ADMA levels in vivo.
  
  
  CONCLUSIONS
  DDAH-1 was positively regulated by losartan and pentoxifylline with its antioxidative effect in albumin-exposed renal proximal tubular cells. Combined treatment with losartan and pentoxifylline has a direct beneficial effect on expression of renal DDAH-1, and, thus, at least in part, modulates the circulatory levels of ADMA in proteinuric nephropathy.
authors: Division of Nephrology and Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea. sh-park@knu.ac.kr
authors: Sun-Hee
authors: SH
authors: Park
authors: Seung Hyea
authors: SH
authors: Hyun
authors: Hye-Myung
authors: HM
authors: Ryu
authors: Ji-Sun
authors: JS
authors: Ahn
authors: Se-Hyun
authors: SH
authors: Oh
authors: Eun-Joo
authors: EJ
authors: Oh
authors: Se-Hee
authors: SH
authors: Yoon
authors: Ji-Young
authors: JY
authors: Choi
authors: Jang-Hee
authors: JH
authors: Cho
authors: Chan-Duck
authors: CD
authors: Kim
authors: Yong-Lim
authors: YL
authors: Kim
mesh_terms: D000118:Acetylglucosaminidase / Q000378:metabolism; D000419:Albuminuria / Q000188:drug therapy / Q000201:enzymology*; D000581:Amidohydrolases / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism; D002460:Cell Line; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000201:enzymology; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D010431:Pentoxifylline / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; C018524:N,N-dimethylarginine; D001120:Arginine; D000118:Acetylglucosaminidase; D000581:Amidohydrolases; C059999:dimethylargininase; D019808:Losartan; D010431:Pentoxifylline