Mineralocorticoid receptor antagonism attenuates glomerular filtration barrier remodeling in the transgenic Ren2 rat
1 Internal Medicine, 2 Physiology and Pharmacology, and 3 Diabetes Cardiovascular Center, University of Missouri-Columbia School of Medicine and 4 College of Veterinary Medicine, University of Missouri, Columbia, Missouri; 5 Wake Forest University, Winston-Salem, North Carolina; and 6 Harry S. Truma...
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| Veröffentlicht in: | American Journal of Physiology - Renal Physiology 2009-05, Vol.296 (5), p.F1013-F1022 |
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| creator | Whaley-Connell, Adam Habibi, Javad Wei, Yongzhong Gutweiler, Alex Jellison, Jessica Wiedmeyer, Charles E Ferrario, Carlos M Sowers, James R |
| description | 1 Internal Medicine, 2 Physiology and Pharmacology, and 3 Diabetes Cardiovascular Center, University of Missouri-Columbia School of Medicine and 4 College of Veterinary Medicine, University of Missouri, Columbia, Missouri; 5 Wake Forest University, Winston-Salem, North Carolina; and 6 Harry S. Truman Department of Veterans Affairs Medical Center, Columbia, Missouri
Submitted 24 October 2008
; accepted in final form 3 March 2009
Recent evidence suggests that mineralocorticoid receptor (MR) antagonism has beneficial effects on tissue oxidative stress and insulin metabolic signaling as well as reducing proteinuria. However, the mechanisms by which MR antagonism corrects both renin-angiotensin-aldosterone system (RAAS) impairments in renal insulin metabolic signaling and filtration barrier/podocyte injury remain unknown. To explore this potential beneficial interactive effect of MR antagonism we used young transgenic (mRen2)27 (Ren2) rats with increased tissue RAAS activity and elevated serum aldosterone levels. Ren2 and age-matched Sprague-Dawley (SD) control rats (age 6–7 wk) were implanted with a low dose of the MR antagonist spironolactone (0.24 mg/day) or vehicle, both delivered over 21 days. Albuminuria, podocyte-specific proteins (synaptopodin, nephrin, and podocin), and ultrastructural analysis of the glomerular filtration barrier were measured in relation to RAAS activation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, reactive oxygen species (ROS), and the redox-sensitive Rho kinase (ROK). Insulin metabolic signaling was determined via measurement of insulin receptor substrate-1 (IRS-1) phosphorylation, IRS-1 ubiquitin/proteasomal degradation, and phosphorylation of Akt. Ren2 rats exhibited albuminuria, loss of podocyte-specific proteins, and podocyte foot process effacement contemporaneous with reduced renal IRS-1 and protein kinase B/Akt phosphorylation compared with SD control rats (each P < 0.05). Ren2 kidneys also manifested increased NADPH oxidase/ROS/ROK in conjunction with enhanced renal tissue levels of angiotensin II (ANG II), ANG-(1-12), and angiotensin type 1 receptor. Low-dose spironolactone treatment reduced albuminuria and tissue RAAS activity and improved podocyte structural and protein integrity with improvements in IRS-1/Akt phosphorylation. Thus, in this model of RAAS activation, MR antagonism attenuates glomerular/podocyte remodeling and albuminuria, in part through reductions in redox-mediated impairment |
| doi_str_mv | 10.1152/ajprenal.90646.2008 |
| format | Article |
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Submitted 24 October 2008
; accepted in final form 3 March 2009
Recent evidence suggests that mineralocorticoid receptor (MR) antagonism has beneficial effects on tissue oxidative stress and insulin metabolic signaling as well as reducing proteinuria. However, the mechanisms by which MR antagonism corrects both renin-angiotensin-aldosterone system (RAAS) impairments in renal insulin metabolic signaling and filtration barrier/podocyte injury remain unknown. To explore this potential beneficial interactive effect of MR antagonism we used young transgenic (mRen2)27 (Ren2) rats with increased tissue RAAS activity and elevated serum aldosterone levels. Ren2 and age-matched Sprague-Dawley (SD) control rats (age 6–7 wk) were implanted with a low dose of the MR antagonist spironolactone (0.24 mg/day) or vehicle, both delivered over 21 days. Albuminuria, podocyte-specific proteins (synaptopodin, nephrin, and podocin), and ultrastructural analysis of the glomerular filtration barrier were measured in relation to RAAS activation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, reactive oxygen species (ROS), and the redox-sensitive Rho kinase (ROK). Insulin metabolic signaling was determined via measurement of insulin receptor substrate-1 (IRS-1) phosphorylation, IRS-1 ubiquitin/proteasomal degradation, and phosphorylation of Akt. Ren2 rats exhibited albuminuria, loss of podocyte-specific proteins, and podocyte foot process effacement contemporaneous with reduced renal IRS-1 and protein kinase B/Akt phosphorylation compared with SD control rats (each P < 0.05). Ren2 kidneys also manifested increased NADPH oxidase/ROS/ROK in conjunction with enhanced renal tissue levels of angiotensin II (ANG II), ANG-(1-12), and angiotensin type 1 receptor. Low-dose spironolactone treatment reduced albuminuria and tissue RAAS activity and improved podocyte structural and protein integrity with improvements in IRS-1/Akt phosphorylation. Thus, in this model of RAAS activation, MR antagonism attenuates glomerular/podocyte remodeling and albuminuria, in part through reductions in redox-mediated impairment of insulin metabolic signaling.
renal mineralocorticoid receptor; reduced nicotinamide adenine dinucleotide phosphate oxidase; oxidative stress; podocyte
Address for reprint requests and other correspondence: A. Whaley-Connell, Univ. of Missouri-Columbia School of Medicine, CE417, DC043.0, 5 Hospital Dr, Columbia, MO 65212 (e-mail: whaleyconnella{at}health.missouri.edu )</description><identifier>ISSN: 0363-6127</identifier><identifier>ISSN: 1931-857X</identifier><identifier>EISSN: 2161-1157</identifier><identifier>EISSN: 1522-1466</identifier><identifier>DOI: 10.1152/ajprenal.90646.2008</identifier><identifier>PMID: 19261739</identifier><language>eng</language><publisher>United States: American Physiological Society</publisher><subject>Albuminuria - drug therapy ; Albuminuria - physiopathology ; Animals ; Biochemistry ; Blood Pressure - drug effects ; Blood Pressure - physiology ; Dose-Response Relationship, Drug ; Glomerular Filtration Rate - drug effects ; Glomerular Filtration Rate - physiology ; Insulin ; Insulin Receptor Substrate Proteins - metabolism ; Kidney Glomerulus - cytology ; Kidney Glomerulus - drug effects ; Kidney Glomerulus - physiology ; Kinases ; Metabolism ; Mineralocorticoid Receptor Antagonists - pharmacology ; NADH, NADPH Oxidoreductases - metabolism ; NADPH Oxidase 1 ; Oxidation ; Oxidative Stress - physiology ; Phosphorylation - drug effects ; Podocytes - drug effects ; Podocytes - physiology ; Proto-Oncogene Proteins c-akt - metabolism ; Rats ; Rats, Sprague-Dawley ; Rats, Transgenic ; Reactive Oxygen Species - metabolism ; Receptors, Mineralocorticoid - metabolism ; Renin - genetics ; Renin-Angiotensin System - physiology ; Rodents ; Spironolactone - pharmacology ; Tissues</subject><ispartof>American Journal of Physiology - Renal Physiology, 2009-05, Vol.296 (5), p.F1013-F1022</ispartof><rights>Copyright American Physiological Society May 2009</rights><rights>Copyright © 2009, American Physiological Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c536t-a3a60a93ceb347e7c683d2c5edb60b1cdcc98a6deb0844fd8bc8a5d5f60a6f213</citedby><cites>FETCH-LOGICAL-c536t-a3a60a93ceb347e7c683d2c5edb60b1cdcc98a6deb0844fd8bc8a5d5f60a6f213</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,777,781,882,3026,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19261739$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Whaley-Connell, Adam</creatorcontrib><creatorcontrib>Habibi, Javad</creatorcontrib><creatorcontrib>Wei, Yongzhong</creatorcontrib><creatorcontrib>Gutweiler, Alex</creatorcontrib><creatorcontrib>Jellison, Jessica</creatorcontrib><creatorcontrib>Wiedmeyer, Charles E</creatorcontrib><creatorcontrib>Ferrario, Carlos M</creatorcontrib><creatorcontrib>Sowers, James R</creatorcontrib><title>Mineralocorticoid receptor antagonism attenuates glomerular filtration barrier remodeling in the transgenic Ren2 rat</title><title>American Journal of Physiology - Renal Physiology</title><addtitle>Am J Physiol Renal Physiol</addtitle><description>1 Internal Medicine, 2 Physiology and Pharmacology, and 3 Diabetes Cardiovascular Center, University of Missouri-Columbia School of Medicine and 4 College of Veterinary Medicine, University of Missouri, Columbia, Missouri; 5 Wake Forest University, Winston-Salem, North Carolina; and 6 Harry S. Truman Department of Veterans Affairs Medical Center, Columbia, Missouri
Submitted 24 October 2008
; accepted in final form 3 March 2009
Recent evidence suggests that mineralocorticoid receptor (MR) antagonism has beneficial effects on tissue oxidative stress and insulin metabolic signaling as well as reducing proteinuria. However, the mechanisms by which MR antagonism corrects both renin-angiotensin-aldosterone system (RAAS) impairments in renal insulin metabolic signaling and filtration barrier/podocyte injury remain unknown. To explore this potential beneficial interactive effect of MR antagonism we used young transgenic (mRen2)27 (Ren2) rats with increased tissue RAAS activity and elevated serum aldosterone levels. Ren2 and age-matched Sprague-Dawley (SD) control rats (age 6–7 wk) were implanted with a low dose of the MR antagonist spironolactone (0.24 mg/day) or vehicle, both delivered over 21 days. Albuminuria, podocyte-specific proteins (synaptopodin, nephrin, and podocin), and ultrastructural analysis of the glomerular filtration barrier were measured in relation to RAAS activation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, reactive oxygen species (ROS), and the redox-sensitive Rho kinase (ROK). Insulin metabolic signaling was determined via measurement of insulin receptor substrate-1 (IRS-1) phosphorylation, IRS-1 ubiquitin/proteasomal degradation, and phosphorylation of Akt. Ren2 rats exhibited albuminuria, loss of podocyte-specific proteins, and podocyte foot process effacement contemporaneous with reduced renal IRS-1 and protein kinase B/Akt phosphorylation compared with SD control rats (each P < 0.05). Ren2 kidneys also manifested increased NADPH oxidase/ROS/ROK in conjunction with enhanced renal tissue levels of angiotensin II (ANG II), ANG-(1-12), and angiotensin type 1 receptor. Low-dose spironolactone treatment reduced albuminuria and tissue RAAS activity and improved podocyte structural and protein integrity with improvements in IRS-1/Akt phosphorylation. Thus, in this model of RAAS activation, MR antagonism attenuates glomerular/podocyte remodeling and albuminuria, in part through reductions in redox-mediated impairment of insulin metabolic signaling.
renal mineralocorticoid receptor; reduced nicotinamide adenine dinucleotide phosphate oxidase; oxidative stress; podocyte
Address for reprint requests and other correspondence: A. Whaley-Connell, Univ. of Missouri-Columbia School of Medicine, CE417, DC043.0, 5 Hospital Dr, Columbia, MO 65212 (e-mail: whaleyconnella{at}health.missouri.edu )</description><subject>Albuminuria - drug therapy</subject><subject>Albuminuria - physiopathology</subject><subject>Animals</subject><subject>Biochemistry</subject><subject>Blood Pressure - drug effects</subject><subject>Blood Pressure - physiology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Glomerular Filtration Rate - drug effects</subject><subject>Glomerular Filtration Rate - physiology</subject><subject>Insulin</subject><subject>Insulin Receptor Substrate Proteins - metabolism</subject><subject>Kidney Glomerulus - cytology</subject><subject>Kidney Glomerulus - drug effects</subject><subject>Kidney Glomerulus - physiology</subject><subject>Kinases</subject><subject>Metabolism</subject><subject>Mineralocorticoid Receptor Antagonists - pharmacology</subject><subject>NADH, NADPH Oxidoreductases - metabolism</subject><subject>NADPH Oxidase 1</subject><subject>Oxidation</subject><subject>Oxidative Stress - physiology</subject><subject>Phosphorylation - drug effects</subject><subject>Podocytes - drug effects</subject><subject>Podocytes - physiology</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Rats, Transgenic</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Receptors, Mineralocorticoid - metabolism</subject><subject>Renin - genetics</subject><subject>Renin-Angiotensin System - physiology</subject><subject>Rodents</subject><subject>Spironolactone - pharmacology</subject><subject>Tissues</subject><issn>0363-6127</issn><issn>1931-857X</issn><issn>2161-1157</issn><issn>1522-1466</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkU9v1DAQxS1ERZfCJ0BCFvds_WfjJBckVFFAKqpUlbPl2JPEK8cOtgPab4-XXSic5jDv9-ZpHkJvKNlSWrNrtV8ieOW2HRE7sWWEtM_QhlFBq7JvnqMN4YJXgrLmEr1MaU8IY6IVL9Al7ZigDe82KH-1HqJyQYeYrQ7W4AgalhwiVj6rMXibZqxyBr-qDAmPLswQV6ciHqzLUWUbPO5VjBZigedgwFk_YutxngAXhU8jeKvxA3iGC_AKXQzKJXh9nlfo2-3Hx5vP1d39py83H-4qXXORK8WVIKrjGnq-a6DRouWG6RpML0hPtdG6a5Uw0JN2txtM2-tW1aYeCiUGRvkVen_yXdZ-BqPBlzBOLtHOKh5kUFb-v_F2kmP4IcubKBdNMXh3Nojh-wopy31YY_l5kowTSiivRRHxk0jHkFKE4e8BSuSxKfmnKfm7KXlsqlBv_832xJyrKYLrk2Cy4_TTRpDLdEg2uDAenhxZJ2Qtb49R-C9qyaey</recordid><startdate>20090501</startdate><enddate>20090501</enddate><creator>Whaley-Connell, Adam</creator><creator>Habibi, Javad</creator><creator>Wei, Yongzhong</creator><creator>Gutweiler, Alex</creator><creator>Jellison, Jessica</creator><creator>Wiedmeyer, Charles E</creator><creator>Ferrario, Carlos M</creator><creator>Sowers, James R</creator><general>American Physiological Society</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>5PM</scope></search><sort><creationdate>20090501</creationdate><title>Mineralocorticoid receptor antagonism attenuates glomerular filtration barrier remodeling in the transgenic Ren2 rat</title><author>Whaley-Connell, Adam ; Habibi, Javad ; Wei, Yongzhong ; Gutweiler, Alex ; Jellison, Jessica ; Wiedmeyer, Charles E ; Ferrario, Carlos M ; Sowers, James R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c536t-a3a60a93ceb347e7c683d2c5edb60b1cdcc98a6deb0844fd8bc8a5d5f60a6f213</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Albuminuria - drug therapy</topic><topic>Albuminuria - physiopathology</topic><topic>Animals</topic><topic>Biochemistry</topic><topic>Blood Pressure - drug effects</topic><topic>Blood Pressure - physiology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Glomerular Filtration Rate - drug effects</topic><topic>Glomerular Filtration Rate - physiology</topic><topic>Insulin</topic><topic>Insulin Receptor Substrate Proteins - metabolism</topic><topic>Kidney Glomerulus - cytology</topic><topic>Kidney Glomerulus - drug effects</topic><topic>Kidney Glomerulus - physiology</topic><topic>Kinases</topic><topic>Metabolism</topic><topic>Mineralocorticoid Receptor Antagonists - pharmacology</topic><topic>NADH, NADPH Oxidoreductases - metabolism</topic><topic>NADPH Oxidase 1</topic><topic>Oxidation</topic><topic>Oxidative Stress - physiology</topic><topic>Phosphorylation - drug effects</topic><topic>Podocytes - drug effects</topic><topic>Podocytes - physiology</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Rats, Transgenic</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Receptors, Mineralocorticoid - metabolism</topic><topic>Renin - genetics</topic><topic>Renin-Angiotensin System - physiology</topic><topic>Rodents</topic><topic>Spironolactone - pharmacology</topic><topic>Tissues</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Whaley-Connell, Adam</creatorcontrib><creatorcontrib>Habibi, Javad</creatorcontrib><creatorcontrib>Wei, Yongzhong</creatorcontrib><creatorcontrib>Gutweiler, Alex</creatorcontrib><creatorcontrib>Jellison, Jessica</creatorcontrib><creatorcontrib>Wiedmeyer, Charles E</creatorcontrib><creatorcontrib>Ferrario, Carlos M</creatorcontrib><creatorcontrib>Sowers, James R</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>American Journal of Physiology - Renal Physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Whaley-Connell, Adam</au><au>Habibi, Javad</au><au>Wei, Yongzhong</au><au>Gutweiler, Alex</au><au>Jellison, Jessica</au><au>Wiedmeyer, Charles E</au><au>Ferrario, Carlos M</au><au>Sowers, James R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mineralocorticoid receptor antagonism attenuates glomerular filtration barrier remodeling in the transgenic Ren2 rat</atitle><jtitle>American Journal of Physiology - Renal Physiology</jtitle><addtitle>Am J Physiol Renal Physiol</addtitle><date>2009-05-01</date><risdate>2009</risdate><volume>296</volume><issue>5</issue><spage>F1013</spage><epage>F1022</epage><pages>F1013-F1022</pages><issn>0363-6127</issn><issn>1931-857X</issn><eissn>2161-1157</eissn><eissn>1522-1466</eissn><abstract>1 Internal Medicine, 2 Physiology and Pharmacology, and 3 Diabetes Cardiovascular Center, University of Missouri-Columbia School of Medicine and 4 College of Veterinary Medicine, University of Missouri, Columbia, Missouri; 5 Wake Forest University, Winston-Salem, North Carolina; and 6 Harry S. Truman Department of Veterans Affairs Medical Center, Columbia, Missouri
Submitted 24 October 2008
; accepted in final form 3 March 2009
Recent evidence suggests that mineralocorticoid receptor (MR) antagonism has beneficial effects on tissue oxidative stress and insulin metabolic signaling as well as reducing proteinuria. However, the mechanisms by which MR antagonism corrects both renin-angiotensin-aldosterone system (RAAS) impairments in renal insulin metabolic signaling and filtration barrier/podocyte injury remain unknown. To explore this potential beneficial interactive effect of MR antagonism we used young transgenic (mRen2)27 (Ren2) rats with increased tissue RAAS activity and elevated serum aldosterone levels. Ren2 and age-matched Sprague-Dawley (SD) control rats (age 6–7 wk) were implanted with a low dose of the MR antagonist spironolactone (0.24 mg/day) or vehicle, both delivered over 21 days. Albuminuria, podocyte-specific proteins (synaptopodin, nephrin, and podocin), and ultrastructural analysis of the glomerular filtration barrier were measured in relation to RAAS activation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, reactive oxygen species (ROS), and the redox-sensitive Rho kinase (ROK). Insulin metabolic signaling was determined via measurement of insulin receptor substrate-1 (IRS-1) phosphorylation, IRS-1 ubiquitin/proteasomal degradation, and phosphorylation of Akt. Ren2 rats exhibited albuminuria, loss of podocyte-specific proteins, and podocyte foot process effacement contemporaneous with reduced renal IRS-1 and protein kinase B/Akt phosphorylation compared with SD control rats (each P < 0.05). Ren2 kidneys also manifested increased NADPH oxidase/ROS/ROK in conjunction with enhanced renal tissue levels of angiotensin II (ANG II), ANG-(1-12), and angiotensin type 1 receptor. Low-dose spironolactone treatment reduced albuminuria and tissue RAAS activity and improved podocyte structural and protein integrity with improvements in IRS-1/Akt phosphorylation. Thus, in this model of RAAS activation, MR antagonism attenuates glomerular/podocyte remodeling and albuminuria, in part through reductions in redox-mediated impairment of insulin metabolic signaling.
renal mineralocorticoid receptor; reduced nicotinamide adenine dinucleotide phosphate oxidase; oxidative stress; podocyte
Address for reprint requests and other correspondence: A. Whaley-Connell, Univ. of Missouri-Columbia School of Medicine, CE417, DC043.0, 5 Hospital Dr, Columbia, MO 65212 (e-mail: whaleyconnella{at}health.missouri.edu )</abstract><cop>United States</cop><pub>American Physiological Society</pub><pmid>19261739</pmid><doi>10.1152/ajprenal.90646.2008</doi><oa>free_for_read</oa></addata></record> |
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| ispartof | American Journal of Physiology - Renal Physiology, 2009-05, Vol.296 (5), p.F1013-F1022 |
| issn | 0363-6127 1931-857X 2161-1157 1522-1466 |
| language | eng |
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| source | MEDLINE; American Physiological Society; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Albuminuria - drug therapy Albuminuria - physiopathology Animals Biochemistry Blood Pressure - drug effects Blood Pressure - physiology Dose-Response Relationship, Drug Glomerular Filtration Rate - drug effects Glomerular Filtration Rate - physiology Insulin Insulin Receptor Substrate Proteins - metabolism Kidney Glomerulus - cytology Kidney Glomerulus - drug effects Kidney Glomerulus - physiology Kinases Metabolism Mineralocorticoid Receptor Antagonists - pharmacology NADH, NADPH Oxidoreductases - metabolism NADPH Oxidase 1 Oxidation Oxidative Stress - physiology Phosphorylation - drug effects Podocytes - drug effects Podocytes - physiology Proto-Oncogene Proteins c-akt - metabolism Rats Rats, Sprague-Dawley Rats, Transgenic Reactive Oxygen Species - metabolism Receptors, Mineralocorticoid - metabolism Renin - genetics Renin-Angiotensin System - physiology Rodents Spironolactone - pharmacology Tissues |
| title | Mineralocorticoid receptor antagonism attenuates glomerular filtration barrier remodeling in the transgenic Ren2 rat |
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