Effects of losartan and pentoxifylline on renal dimethylarginine dimethylaminohydrolase-1 expression in proteinuric nephropathy

Sun Hee Park, Seung Hyea Hyun, Hye Myung Ryu, Ji Sun Ahn, Se Hyun Oh, Eun Joo Oh, Se Hee Yoon, Ji Young Choi, Jang Hee Cho, Chan Duck Kim, Yong Lim Kim

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Background/Aims: 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)491-500
Number of pages10
JournalAmerican Journal of Nephrology
Volume37
Issue number5
DOIs
StatePublished - May 2013

Keywords

  • Albuminuria
  • Endothelial dysfunction
  • Nephropathy
  • Proximal tubular cells

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