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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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. |
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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 & 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. 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><subject>Acetylglucosaminidase - secretion</subject><subject>Albuminuria - drug therapy</subject><subject>Albuminuria - enzymology</subject><subject>Amidohydrolases - metabolism</subject><subject>Angiotensin II Type 1 Receptor Blockers - pharmacology</subject><subject>Angiotensin II Type 1 Receptor Blockers - therapeutic use</subject><subject>Animals</subject><subject>Arginine - analogs & derivatives</subject><subject>Arginine - metabolism</subject><subject>Cell Line</subject><subject>Free Radical Scavengers - pharmacology</subject><subject>Free Radical Scavengers - therapeutic use</subject><subject>Kidney Tubules, Proximal - drug effects</subject><subject>Kidney Tubules, Proximal - enzymology</subject><subject>Losartan - pharmacology</subject><subject>Losartan - therapeutic use</subject><subject>Original Report: Laboratory Investigation</subject><subject>Oxidative Stress - drug effects</subject><subject>Pentoxifylline - pharmacology</subject><subject>Pentoxifylline - therapeutic use</subject><subject>Rats</subject><subject>Reactive Oxygen Species - metabolism</subject><issn>0250-8095</issn><issn>1421-9670</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNpdkU1v1DAQhi1ERbcLB-4IWeJSDiljO3acIyrLh7RqKwTnyIknrEtip3YidU_8dVztsgdOlsbP80ozLyGvGVwxJusPACAkyJI9IytWclbUqoLnZAVcQqGhlufkIqV7AMY1VC_IORdKSKX4ivzZ9D12c6Khp9uQTJyNp8Zbeod-Do-u3w-D80iDp9_Rm4F-ciPOu_1g4i_nn35Og9H5sNvbGAaTsGB08zhFTMll1Xl6F8OMzi_RdfQGp10Mk8naS3LWmyHhq-O7Jj8_b35cfy22t1--XX_cFp0Q5VxYtL1RgNZaKRUTKIVqda2FFtzYXlS8rqVVupLSgrSVsLquTWvaTmenrcSaXB5ypxgeFkxzM7rU4TAYj2FJDRNKaQ48Z6_Ju__Q-7DEvHumSqY0lJqVmXp_oLoYUorYN1N0o4n7hkHz1EpzaiWzb4-JSzuiPZH_asjAmwPwO58V4wk4-n8BAd2SRw</recordid><startdate>20130101</startdate><enddate>20130101</enddate><creator>Park, Sun-Hee</creator><creator>Hyun, Seung Hyea</creator><creator>Ryu, Hye-Myung</creator><creator>Ahn, Ji-Sun</creator><creator>Oh, Se-Hyun</creator><creator>Oh, Eun-Joo</creator><creator>Yoon, Se-Hee</creator><creator>Choi, Ji-Young</creator><creator>Cho, Jang-Hee</creator><creator>Kim, Chan-Duck</creator><creator>Kim, Yong-Lim</creator><general>S. 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secretion</topic><topic>Albuminuria - drug therapy</topic><topic>Albuminuria - enzymology</topic><topic>Amidohydrolases - metabolism</topic><topic>Angiotensin II Type 1 Receptor Blockers - pharmacology</topic><topic>Angiotensin II Type 1 Receptor Blockers - therapeutic use</topic><topic>Animals</topic><topic>Arginine - analogs & derivatives</topic><topic>Arginine - metabolism</topic><topic>Cell Line</topic><topic>Free Radical Scavengers - pharmacology</topic><topic>Free Radical Scavengers - therapeutic use</topic><topic>Kidney Tubules, Proximal - drug effects</topic><topic>Kidney Tubules, Proximal - enzymology</topic><topic>Losartan - pharmacology</topic><topic>Losartan - therapeutic use</topic><topic>Original Report: Laboratory Investigation</topic><topic>Oxidative Stress - drug effects</topic><topic>Pentoxifylline - pharmacology</topic><topic>Pentoxifylline - therapeutic use</topic><topic>Rats</topic><topic>Reactive Oxygen Species - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><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><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>SIRS Editorial</collection><collection>MEDLINE - Academic</collection><jtitle>American journal of nephrology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Park, Sun-Hee</au><au>Hyun, Seung Hyea</au><au>Ryu, Hye-Myung</au><au>Ahn, Ji-Sun</au><au>Oh, Se-Hyun</au><au>Oh, Eun-Joo</au><au>Yoon, Se-Hee</au><au>Choi, Ji-Young</au><au>Cho, Jang-Hee</au><au>Kim, Chan-Duck</au><au>Kim, Yong-Lim</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effects of Losartan and Pentoxifylline on Renal Dimethylarginine Dimethylaminohydrolase-1 Expression in Proteinuric Nephropathy</atitle><jtitle>American journal of nephrology</jtitle><addtitle>Am J Nephrol</addtitle><date>2013-01-01</date><risdate>2013</risdate><volume>37</volume><issue>5</issue><spage>491</spage><epage>500</epage><pages>491-500</pages><issn>0250-8095</issn><eissn>1421-9670</eissn><coden>AJNED9</coden><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.</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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