Nephroprotective effects of nebivolol in 2K1C rats through regulation of the kidney ROS-ADMA-NO pathway

To evaluate the protective effect of nebivolol against kidney damage and elucidate the underlying mechanism in a two-kidney, one-clip (2K1C) rat model. 2K1C rats were obtained by clipping left renal artery of male Wistar rats and were considered hypertensive when systolic blood pressure (SBP) was ≥1...

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Veröffentlicht in:Pharmacological reports 2018-10, Vol.70 (5), p.917-929
Hauptverfasser: Wang, Yan, Niu, Mengzhen, Yin, Sha, Zhang, Fei, Shi, Ruizan
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Niu, Mengzhen
Yin, Sha
Zhang, Fei
Shi, Ruizan
description To evaluate the protective effect of nebivolol against kidney damage and elucidate the underlying mechanism in a two-kidney, one-clip (2K1C) rat model. 2K1C rats were obtained by clipping left renal artery of male Wistar rats and were considered hypertensive when systolic blood pressure (SBP) was ≥160mmHg 4 weeks after surgery. The 2K1C hypertensive rats were divided into untreated, nebivolol (10mg/kg, ig), and atenolol (80mg/kg, ig) treatment groups. The treatments lasted for 8 weeks. SBP, kidney structure and function, plasma and kidney angiotensin (Ang) II, nitric oxide (NO), asymmetric dimethylarginine (ADMA), and the oxidant status were examined. Kidney protein expression of NADPH oxidase (Nox) isoforms and its subunit p22phox, nitric oxide synthase (NOS) isoforms, protein arginine N-methyltransferase (PRMT) 1, and dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2 was tested by western blotting. Nebivolol and atenolol exerted similar hypotensive effects. However, atenolol had little effect while nebivolol significantly ameliorated the functional decline and structural damage in the kidney, especially in non-clipped kidney (NCK), which was associated with the reduction of Ang II in NCK. Moreover, nebivolol inhibited the NCK production of reactive oxygen species (ROS) by decreasing Nox2, Nox4, and p22phox expression. Further, nebivolol reduced the plasma and kidney ADMA levels by increasing DDAH2 expression and decreasing PRMT1 expression. Nebivolol also increased the NCK NO level by ameliorating the expression of kidney NOS isoforms. Our results demonstrated that long-term treatment with nebivolol had renoprotective effect in 2K1C rats partly via regulation of kidney ROS-ADMA-NO pathway.
doi_str_mv 10.1016/j.pharep.2018.04.004
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The 2K1C hypertensive rats were divided into untreated, nebivolol (10mg/kg, ig), and atenolol (80mg/kg, ig) treatment groups. The treatments lasted for 8 weeks. SBP, kidney structure and function, plasma and kidney angiotensin (Ang) II, nitric oxide (NO), asymmetric dimethylarginine (ADMA), and the oxidant status were examined. Kidney protein expression of NADPH oxidase (Nox) isoforms and its subunit p22phox, nitric oxide synthase (NOS) isoforms, protein arginine N-methyltransferase (PRMT) 1, and dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2 was tested by western blotting. Nebivolol and atenolol exerted similar hypotensive effects. However, atenolol had little effect while nebivolol significantly ameliorated the functional decline and structural damage in the kidney, especially in non-clipped kidney (NCK), which was associated with the reduction of Ang II in NCK. Moreover, nebivolol inhibited the NCK production of reactive oxygen species (ROS) by decreasing Nox2, Nox4, and p22phox expression. Further, nebivolol reduced the plasma and kidney ADMA levels by increasing DDAH2 expression and decreasing PRMT1 expression. Nebivolol also increased the NCK NO level by ameliorating the expression of kidney NOS isoforms. 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Rep</addtitle><addtitle>Pharmacol Rep</addtitle><description>To evaluate the protective effect of nebivolol against kidney damage and elucidate the underlying mechanism in a two-kidney, one-clip (2K1C) rat model. 2K1C rats were obtained by clipping left renal artery of male Wistar rats and were considered hypertensive when systolic blood pressure (SBP) was ≥160mmHg 4 weeks after surgery. The 2K1C hypertensive rats were divided into untreated, nebivolol (10mg/kg, ig), and atenolol (80mg/kg, ig) treatment groups. The treatments lasted for 8 weeks. SBP, kidney structure and function, plasma and kidney angiotensin (Ang) II, nitric oxide (NO), asymmetric dimethylarginine (ADMA), and the oxidant status were examined. Kidney protein expression of NADPH oxidase (Nox) isoforms and its subunit p22phox, nitric oxide synthase (NOS) isoforms, protein arginine N-methyltransferase (PRMT) 1, and dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2 was tested by western blotting. Nebivolol and atenolol exerted similar hypotensive effects. However, atenolol had little effect while nebivolol significantly ameliorated the functional decline and structural damage in the kidney, especially in non-clipped kidney (NCK), which was associated with the reduction of Ang II in NCK. Moreover, nebivolol inhibited the NCK production of reactive oxygen species (ROS) by decreasing Nox2, Nox4, and p22phox expression. Further, nebivolol reduced the plasma and kidney ADMA levels by increasing DDAH2 expression and decreasing PRMT1 expression. Nebivolol also increased the NCK NO level by ameliorating the expression of kidney NOS isoforms. Our results demonstrated that long-term treatment with nebivolol had renoprotective effect in 2K1C rats partly via regulation of kidney ROS-ADMA-NO pathway.</description><subject>2K1C hypertension</subject><subject>Amidohydrolases - biosynthesis</subject><subject>Angiotensin II - blood</subject><subject>Angiotensin II - metabolism</subject><subject>Animals</subject><subject>Arginine - analogs &amp; derivatives</subject><subject>Arginine - blood</subject><subject>Arginine - metabolism</subject><subject>Atenolol - pharmacology</subject><subject>Blood Pressure - physiology</subject><subject>Drug Safety and Pharmacovigilance</subject><subject>Hypertension, Renovascular - drug therapy</subject><subject>Hypertension, Renovascular - metabolism</subject><subject>Kidney</subject><subject>Kidney - drug effects</subject><subject>Kidney - injuries</subject><subject>Kidney - metabolism</subject><subject>Kidney - pathology</subject><subject>Kidney Function Tests</subject><subject>Male</subject><subject>NADPH Oxidases - biosynthesis</subject><subject>Nebivolol</subject><subject>Nebivolol - pharmacology</subject><subject>Nebivolol - therapeutic use</subject><subject>Nitric Oxide - blood</subject><subject>Nitric Oxide - metabolism</subject><subject>Nitric Oxide Synthase - biosynthesis</subject><subject>Original Article</subject><subject>Pharmacotherapy</subject><subject>Pharmacy</subject><subject>Protective Agents - pharmacology</subject><subject>Protective Agents - therapeutic use</subject><subject>Protein-Arginine N-Methyltransferases - biosynthesis</subject><subject>Rats</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>ROS-ADMA-NO pathway</subject><subject>Signal Transduction - drug effects</subject><issn>1734-1140</issn><issn>2299-5684</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUtv3CAURlHUKpk8_kEUsezGLmD8YFNpNH2kSpqRmnaNML6MmXqMC_ZU8-_DyEmWzQqke74P3QNC15SklNDi4zYdWuVhSBmhVUp4Sgg_QQvGhEjyouLv0IKWGU8o5eQMnYewjQBlWX6KzjJChGCiWqDNAwytd4N3I-jR7gGDMfEWsDO4h9ruXec6bHvM7ugKexUnYwxMmxZ72EydGq3rj_DYAv5jmx4O-Of6MVl-_rFMHtZ4UGP7Tx0u0XujugBXz-cF-v31y6_VbXK__vZ9tbxPNCfVmNAqbxQHgJqJpgBqdM1MIRQoRUVRZ3XFaiDEqEaxnJqyBK7zUnNTk4KLnGQX6MPcGzf6O0EY5c4GDV2nenBTkIxUpRAZZ2VE-Yxq70LwYOTg7U75g6REHhXLrZwVy6NiSbiMBmPs5vmFqd5B8xp6cRqBfAZCHPUb8HLrJt_Hrd8q_jTnIPrZ25gL2kKvobE-_ohsnP1_wROZbqFP</recordid><startdate>20181001</startdate><enddate>20181001</enddate><creator>Wang, Yan</creator><creator>Niu, Mengzhen</creator><creator>Yin, Sha</creator><creator>Zhang, Fei</creator><creator>Shi, Ruizan</creator><general>Elsevier B.V</general><general>Springer International Publishing</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20181001</creationdate><title>Nephroprotective effects of nebivolol in 2K1C rats through regulation of the kidney ROS-ADMA-NO pathway</title><author>Wang, Yan ; Niu, Mengzhen ; Yin, Sha ; Zhang, Fei ; Shi, Ruizan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c408t-185da4eeeb29d6e1fcb2f69aeaa196b3b82be00fada251f77e4c57c4fb0649503</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>2K1C hypertension</topic><topic>Amidohydrolases - biosynthesis</topic><topic>Angiotensin II - blood</topic><topic>Angiotensin II - metabolism</topic><topic>Animals</topic><topic>Arginine - analogs &amp; derivatives</topic><topic>Arginine - blood</topic><topic>Arginine - metabolism</topic><topic>Atenolol - pharmacology</topic><topic>Blood Pressure - physiology</topic><topic>Drug Safety and Pharmacovigilance</topic><topic>Hypertension, Renovascular - drug therapy</topic><topic>Hypertension, Renovascular - metabolism</topic><topic>Kidney</topic><topic>Kidney - drug effects</topic><topic>Kidney - injuries</topic><topic>Kidney - metabolism</topic><topic>Kidney - pathology</topic><topic>Kidney Function Tests</topic><topic>Male</topic><topic>NADPH Oxidases - biosynthesis</topic><topic>Nebivolol</topic><topic>Nebivolol - pharmacology</topic><topic>Nebivolol - therapeutic use</topic><topic>Nitric Oxide - blood</topic><topic>Nitric Oxide - metabolism</topic><topic>Nitric Oxide Synthase - biosynthesis</topic><topic>Original Article</topic><topic>Pharmacotherapy</topic><topic>Pharmacy</topic><topic>Protective Agents - pharmacology</topic><topic>Protective Agents - therapeutic use</topic><topic>Protein-Arginine N-Methyltransferases - biosynthesis</topic><topic>Rats</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>ROS-ADMA-NO pathway</topic><topic>Signal Transduction - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Yan</creatorcontrib><creatorcontrib>Niu, Mengzhen</creatorcontrib><creatorcontrib>Yin, Sha</creatorcontrib><creatorcontrib>Zhang, Fei</creatorcontrib><creatorcontrib>Shi, Ruizan</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Pharmacological reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Yan</au><au>Niu, Mengzhen</au><au>Yin, Sha</au><au>Zhang, Fei</au><au>Shi, Ruizan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nephroprotective effects of nebivolol in 2K1C rats through regulation of the kidney ROS-ADMA-NO pathway</atitle><jtitle>Pharmacological reports</jtitle><stitle>Pharmacol. Rep</stitle><addtitle>Pharmacol Rep</addtitle><date>2018-10-01</date><risdate>2018</risdate><volume>70</volume><issue>5</issue><spage>917</spage><epage>929</epage><pages>917-929</pages><issn>1734-1140</issn><eissn>2299-5684</eissn><abstract>To evaluate the protective effect of nebivolol against kidney damage and elucidate the underlying mechanism in a two-kidney, one-clip (2K1C) rat model. 2K1C rats were obtained by clipping left renal artery of male Wistar rats and were considered hypertensive when systolic blood pressure (SBP) was ≥160mmHg 4 weeks after surgery. The 2K1C hypertensive rats were divided into untreated, nebivolol (10mg/kg, ig), and atenolol (80mg/kg, ig) treatment groups. The treatments lasted for 8 weeks. SBP, kidney structure and function, plasma and kidney angiotensin (Ang) II, nitric oxide (NO), asymmetric dimethylarginine (ADMA), and the oxidant status were examined. Kidney protein expression of NADPH oxidase (Nox) isoforms and its subunit p22phox, nitric oxide synthase (NOS) isoforms, protein arginine N-methyltransferase (PRMT) 1, and dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2 was tested by western blotting. Nebivolol and atenolol exerted similar hypotensive effects. However, atenolol had little effect while nebivolol significantly ameliorated the functional decline and structural damage in the kidney, especially in non-clipped kidney (NCK), which was associated with the reduction of Ang II in NCK. Moreover, nebivolol inhibited the NCK production of reactive oxygen species (ROS) by decreasing Nox2, Nox4, and p22phox expression. Further, nebivolol reduced the plasma and kidney ADMA levels by increasing DDAH2 expression and decreasing PRMT1 expression. Nebivolol also increased the NCK NO level by ameliorating the expression of kidney NOS isoforms. Our results demonstrated that long-term treatment with nebivolol had renoprotective effect in 2K1C rats partly via regulation of kidney ROS-ADMA-NO pathway.</abstract><cop>Cham</cop><pub>Elsevier B.V</pub><pmid>30099298</pmid><doi>10.1016/j.pharep.2018.04.004</doi><tpages>13</tpages></addata></record>
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subjects 2K1C hypertension
Amidohydrolases - biosynthesis
Angiotensin II - blood
Angiotensin II - metabolism
Animals
Arginine - analogs & derivatives
Arginine - blood
Arginine - metabolism
Atenolol - pharmacology
Blood Pressure - physiology
Drug Safety and Pharmacovigilance
Hypertension, Renovascular - drug therapy
Hypertension, Renovascular - metabolism
Kidney
Kidney - drug effects
Kidney - injuries
Kidney - metabolism
Kidney - pathology
Kidney Function Tests
Male
NADPH Oxidases - biosynthesis
Nebivolol
Nebivolol - pharmacology
Nebivolol - therapeutic use
Nitric Oxide - blood
Nitric Oxide - metabolism
Nitric Oxide Synthase - biosynthesis
Original Article
Pharmacotherapy
Pharmacy
Protective Agents - pharmacology
Protective Agents - therapeutic use
Protein-Arginine N-Methyltransferases - biosynthesis
Rats
Reactive Oxygen Species - metabolism
ROS-ADMA-NO pathway
Signal Transduction - drug effects
title Nephroprotective effects of nebivolol in 2K1C rats through regulation of the kidney ROS-ADMA-NO pathway
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