Effects of Losartan and Pentoxifylline on Renal Dimethylarginine Dimethylaminohydrolase-1 Expression in Proteinuric Nephropathy

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 degradin...

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Veröffentlicht in:American journal of nephrology 2013-01, Vol.37 (5), p.491-500
Hauptverfasser: Park, Sun-Hee, Hyun, Seung Hyea, Ryu, Hye-Myung, Ahn, Ji-Sun, Oh, Se-Hyun, Oh, Eun-Joo, Yoon, Se-Hee, Choi, Ji-Young, Cho, Jang-Hee, Kim, Chan-Duck, Kim, Yong-Lim
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container_end_page 500
container_issue 5
container_start_page 491
container_title American journal of nephrology
container_volume 37
creator Park, Sun-Hee
Hyun, Seung Hyea
Ryu, Hye-Myung
Ahn, Ji-Sun
Oh, Se-Hyun
Oh, Eun-Joo
Yoon, Se-Hee
Choi, Ji-Young
Cho, Jang-Hee
Kim, Chan-Duck
Kim, Yong-Lim
description 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.
doi_str_mv 10.1159/000350541
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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.</description><identifier>ISSN: 0250-8095</identifier><identifier>EISSN: 1421-9670</identifier><identifier>DOI: 10.1159/000350541</identifier><identifier>PMID: 23635662</identifier><identifier>CODEN: AJNED9</identifier><language>eng</language><publisher>Basel, Switzerland: S. Karger AG</publisher><subject>Acetylglucosaminidase - secretion ; Albuminuria - drug therapy ; Albuminuria - enzymology ; Amidohydrolases - metabolism ; Angiotensin II Type 1 Receptor Blockers - pharmacology ; Angiotensin II Type 1 Receptor Blockers - therapeutic use ; Animals ; Arginine - analogs &amp; derivatives ; Arginine - metabolism ; Cell Line ; Free Radical Scavengers - pharmacology ; Free Radical Scavengers - therapeutic use ; Kidney Tubules, Proximal - drug effects ; Kidney Tubules, Proximal - enzymology ; Losartan - pharmacology ; Losartan - therapeutic use ; Original Report: Laboratory Investigation ; Oxidative Stress - drug effects ; Pentoxifylline - pharmacology ; Pentoxifylline - therapeutic use ; Rats ; Reactive Oxygen Species - metabolism</subject><ispartof>American journal of nephrology, 2013-01, Vol.37 (5), p.491-500</ispartof><rights>2013 S. Karger AG, Basel</rights><rights>Copyright © 2013 S. Karger AG, Basel.</rights><rights>Copyright (c) 2013 S. Karger AG, Basel</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c334t-dedfa60eddd55613e536b8983832adf372995d68755d05d73d899ababc8eddb73</citedby><cites>FETCH-LOGICAL-c334t-dedfa60eddd55613e536b8983832adf372995d68755d05d73d899ababc8eddb73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,2423,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23635662$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Park, Sun-Hee</creatorcontrib><creatorcontrib>Hyun, Seung Hyea</creatorcontrib><creatorcontrib>Ryu, Hye-Myung</creatorcontrib><creatorcontrib>Ahn, Ji-Sun</creatorcontrib><creatorcontrib>Oh, Se-Hyun</creatorcontrib><creatorcontrib>Oh, Eun-Joo</creatorcontrib><creatorcontrib>Yoon, Se-Hee</creatorcontrib><creatorcontrib>Choi, Ji-Young</creatorcontrib><creatorcontrib>Cho, Jang-Hee</creatorcontrib><creatorcontrib>Kim, Chan-Duck</creatorcontrib><creatorcontrib>Kim, Yong-Lim</creatorcontrib><title>Effects of Losartan and Pentoxifylline on Renal Dimethylarginine Dimethylaminohydrolase-1 Expression in Proteinuric Nephropathy</title><title>American journal of nephrology</title><addtitle>Am J Nephrol</addtitle><description>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. 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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.</abstract><cop>Basel, Switzerland</cop><pub>S. Karger AG</pub><pmid>23635662</pmid><doi>10.1159/000350541</doi><tpages>10</tpages></addata></record>
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subjects Acetylglucosaminidase - secretion
Albuminuria - drug therapy
Albuminuria - enzymology
Amidohydrolases - metabolism
Angiotensin II Type 1 Receptor Blockers - pharmacology
Angiotensin II Type 1 Receptor Blockers - therapeutic use
Animals
Arginine - analogs & derivatives
Arginine - metabolism
Cell Line
Free Radical Scavengers - pharmacology
Free Radical Scavengers - therapeutic use
Kidney Tubules, Proximal - drug effects
Kidney Tubules, Proximal - enzymology
Losartan - pharmacology
Losartan - therapeutic use
Original Report: Laboratory Investigation
Oxidative Stress - drug effects
Pentoxifylline - pharmacology
Pentoxifylline - therapeutic use
Rats
Reactive Oxygen Species - metabolism
title Effects of Losartan and Pentoxifylline on Renal Dimethylarginine Dimethylaminohydrolase-1 Expression in Proteinuric Nephropathy
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