mTORC1/2 and rapamycin in female Han:SPRD rats with polycystic kidney disease

Rapamycin slows disease progression in the male Han:SPRD (Cy/+) rat with polycystic kidney disease (PKD). The aim of this study was to determine the effect of rapamycin on PKD and the relative contributions of the proproliferative mammalian target of rapamycin complexes 1 and 2 (mTORC1 and mTORC2) i...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:American Journal of Physiology - Renal Physiology 2011-01, Vol.300 (1), p.F236-F244
Hauptverfasser: Belibi, Franck, Ravichandran, Kameswaran, Zafar, Iram, He, Zhibin, Edelstein, Charles L
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page F244
container_issue 1
container_start_page F236
container_title American Journal of Physiology - Renal Physiology
container_volume 300
creator Belibi, Franck
Ravichandran, Kameswaran
Zafar, Iram
He, Zhibin
Edelstein, Charles L
description Rapamycin slows disease progression in the male Han:SPRD (Cy/+) rat with polycystic kidney disease (PKD). The aim of this study was to determine the effect of rapamycin on PKD and the relative contributions of the proproliferative mammalian target of rapamycin complexes 1 and 2 (mTORC1 and mTORC2) in female Cy/+ rats. Female Cy/+ rats were treated with rapamycin from 4 to 12 wk of age. In vehicle-treated Cy/+ rats, kidney volume increased by 40% and cyst volume density (CVD) was 19%. Phosphorylated S6 (p-S6) ribosomal protein, a marker of mTORC1 activity, was increased in Cy/+ rats compared with normal littermate controls (+/+) and decreased by rapamycin. Despite activation of mTORC1 in female Cy/+ rats, rapamycin had no effect on kidney size, CVD, number of PCNA-positive cystic tubular cells, caspase-3 activity, or the number of terminal deoxynucleotidyl transferase dUTP-mediated nick-end label-positive apoptotic cells. To determine a reason for the lack of effect of rapamycin, we studied the mTORC2 signaling pathway. On immunoblot of kidney, phosphorylated (Ser473) Akt (p-Akt), a marker of mTORC2 activity, was increased in female Cy/+ rats treated with rapamycin. Phosphorylated (Ser657) PKCα, a substrate of mTORC2, was unaffected by rapamycin in females. In contrast, in male rats, where rapamycin significantly decreases PKD, p-Akt (Ser473) was decreased by rapamcyin. PKCα (Ser657) was increased in male Cy/+ rats but was unaffected by rapamycin. In summary, in female Cy/+ rats, rapamycin had no effect on PKD and proproliferative p-Akt (Ser473) activity was increased by rapamycin. There were differential effects of rapamycin on mTORC2 signaling in female vs. male Cy/+ rats.
doi_str_mv 10.1152/ajprenal.00129.2010
format Article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3023230</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2238005181</sourcerecordid><originalsourceid>FETCH-LOGICAL-c431t-f60668e4fd56fd9849a9995bc2bdfaff966baefa0ebd6c022dbc0d816a8b26b03</originalsourceid><addsrcrecordid>eNpdkVtLHDEYhkNR6qH9BQUZvPFq1i_JTHbihSBrq4JisRZ6F77JQbOdk8lsZf59s56ohUAC7_O9JHkI-UJhRmnJDnE5BNthMwOgTM4YUPhAtlPCcloIsZHOktO8Kue_tshOjEtIIGX0I9liIAs-n8M2uWpvr28W9JBl2Jks4IDtpH2XpeVsi43NzrE7-vH95jSFY8we_XifDX0z6SmOXme_venslBkfLUb7iWw6bKL9_LLvkp_fvt4uzvPL67OLxcllrgtOx9wJEKKyhTOlcEZWhUQpZVlrVhuHzkkharQOwdZGaGDM1BpMRQVWNRM18F1y_Nw7rOrWGm27MWCjhuBbDJPq0av3Sefv1V3_R3FgnPF1wcFLQegfVjaOqvVR26bBzvarqCrGJHCAKpH7_5HLfhXStyeIyzlnJS0SxJ8hHfoYg3VvV6Gg1rLUqyz1JEutZaWpvX9f8Tbzaof_BcJzkwE</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>839732514</pqid></control><display><type>article</type><title>mTORC1/2 and rapamycin in female Han:SPRD rats with polycystic kidney disease</title><source>MEDLINE</source><source>American Physiological Society</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Alma/SFX Local Collection</source><creator>Belibi, Franck ; Ravichandran, Kameswaran ; Zafar, Iram ; He, Zhibin ; Edelstein, Charles L</creator><creatorcontrib>Belibi, Franck ; Ravichandran, Kameswaran ; Zafar, Iram ; He, Zhibin ; Edelstein, Charles L</creatorcontrib><description>Rapamycin slows disease progression in the male Han:SPRD (Cy/+) rat with polycystic kidney disease (PKD). The aim of this study was to determine the effect of rapamycin on PKD and the relative contributions of the proproliferative mammalian target of rapamycin complexes 1 and 2 (mTORC1 and mTORC2) in female Cy/+ rats. Female Cy/+ rats were treated with rapamycin from 4 to 12 wk of age. In vehicle-treated Cy/+ rats, kidney volume increased by 40% and cyst volume density (CVD) was 19%. Phosphorylated S6 (p-S6) ribosomal protein, a marker of mTORC1 activity, was increased in Cy/+ rats compared with normal littermate controls (+/+) and decreased by rapamycin. Despite activation of mTORC1 in female Cy/+ rats, rapamycin had no effect on kidney size, CVD, number of PCNA-positive cystic tubular cells, caspase-3 activity, or the number of terminal deoxynucleotidyl transferase dUTP-mediated nick-end label-positive apoptotic cells. To determine a reason for the lack of effect of rapamycin, we studied the mTORC2 signaling pathway. On immunoblot of kidney, phosphorylated (Ser473) Akt (p-Akt), a marker of mTORC2 activity, was increased in female Cy/+ rats treated with rapamycin. Phosphorylated (Ser657) PKCα, a substrate of mTORC2, was unaffected by rapamycin in females. In contrast, in male rats, where rapamycin significantly decreases PKD, p-Akt (Ser473) was decreased by rapamcyin. PKCα (Ser657) was increased in male Cy/+ rats but was unaffected by rapamycin. In summary, in female Cy/+ rats, rapamycin had no effect on PKD and proproliferative p-Akt (Ser473) activity was increased by rapamycin. There were differential effects of rapamycin on mTORC2 signaling in female vs. male Cy/+ rats.</description><identifier>ISSN: 1931-857X</identifier><identifier>ISSN: 0363-6127</identifier><identifier>EISSN: 1522-1466</identifier><identifier>DOI: 10.1152/ajprenal.00129.2010</identifier><identifier>PMID: 20943770</identifier><language>eng</language><publisher>United States: American Physiological Society</publisher><subject>Animals ; Apoptosis ; Caspase 3 - metabolism ; Drugs ; Female ; Kidney diseases ; Nephrology ; Pharmacology ; Phosphorylation ; Polycystic Kidney, Autosomal Dominant - drug therapy ; Polycystic Kidney, Autosomal Dominant - metabolism ; Polycystic Kidney, Autosomal Dominant - pathology ; Protein Kinase C-alpha - metabolism ; Proto-Oncogene Proteins c-akt - metabolism ; Rats ; Ribosomal Protein S6 - metabolism ; Rodents ; Sex Characteristics ; Sirolimus - metabolism ; Sirolimus - therapeutic use ; TOR Serine-Threonine Kinases - metabolism</subject><ispartof>American Journal of Physiology - Renal Physiology, 2011-01, Vol.300 (1), p.F236-F244</ispartof><rights>Copyright American Physiological Society Jan 2011</rights><rights>Copyright © 2011 the American Physiological Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c431t-f60668e4fd56fd9849a9995bc2bdfaff966baefa0ebd6c022dbc0d816a8b26b03</citedby><cites>FETCH-LOGICAL-c431t-f60668e4fd56fd9849a9995bc2bdfaff966baefa0ebd6c022dbc0d816a8b26b03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3026,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20943770$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Belibi, Franck</creatorcontrib><creatorcontrib>Ravichandran, Kameswaran</creatorcontrib><creatorcontrib>Zafar, Iram</creatorcontrib><creatorcontrib>He, Zhibin</creatorcontrib><creatorcontrib>Edelstein, Charles L</creatorcontrib><title>mTORC1/2 and rapamycin in female Han:SPRD rats with polycystic kidney disease</title><title>American Journal of Physiology - Renal Physiology</title><addtitle>Am J Physiol Renal Physiol</addtitle><description>Rapamycin slows disease progression in the male Han:SPRD (Cy/+) rat with polycystic kidney disease (PKD). The aim of this study was to determine the effect of rapamycin on PKD and the relative contributions of the proproliferative mammalian target of rapamycin complexes 1 and 2 (mTORC1 and mTORC2) in female Cy/+ rats. Female Cy/+ rats were treated with rapamycin from 4 to 12 wk of age. In vehicle-treated Cy/+ rats, kidney volume increased by 40% and cyst volume density (CVD) was 19%. Phosphorylated S6 (p-S6) ribosomal protein, a marker of mTORC1 activity, was increased in Cy/+ rats compared with normal littermate controls (+/+) and decreased by rapamycin. Despite activation of mTORC1 in female Cy/+ rats, rapamycin had no effect on kidney size, CVD, number of PCNA-positive cystic tubular cells, caspase-3 activity, or the number of terminal deoxynucleotidyl transferase dUTP-mediated nick-end label-positive apoptotic cells. To determine a reason for the lack of effect of rapamycin, we studied the mTORC2 signaling pathway. On immunoblot of kidney, phosphorylated (Ser473) Akt (p-Akt), a marker of mTORC2 activity, was increased in female Cy/+ rats treated with rapamycin. Phosphorylated (Ser657) PKCα, a substrate of mTORC2, was unaffected by rapamycin in females. In contrast, in male rats, where rapamycin significantly decreases PKD, p-Akt (Ser473) was decreased by rapamcyin. PKCα (Ser657) was increased in male Cy/+ rats but was unaffected by rapamycin. In summary, in female Cy/+ rats, rapamycin had no effect on PKD and proproliferative p-Akt (Ser473) activity was increased by rapamycin. There were differential effects of rapamycin on mTORC2 signaling in female vs. male Cy/+ rats.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Caspase 3 - metabolism</subject><subject>Drugs</subject><subject>Female</subject><subject>Kidney diseases</subject><subject>Nephrology</subject><subject>Pharmacology</subject><subject>Phosphorylation</subject><subject>Polycystic Kidney, Autosomal Dominant - drug therapy</subject><subject>Polycystic Kidney, Autosomal Dominant - metabolism</subject><subject>Polycystic Kidney, Autosomal Dominant - pathology</subject><subject>Protein Kinase C-alpha - metabolism</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Rats</subject><subject>Ribosomal Protein S6 - metabolism</subject><subject>Rodents</subject><subject>Sex Characteristics</subject><subject>Sirolimus - metabolism</subject><subject>Sirolimus - therapeutic use</subject><subject>TOR Serine-Threonine Kinases - metabolism</subject><issn>1931-857X</issn><issn>0363-6127</issn><issn>1522-1466</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkVtLHDEYhkNR6qH9BQUZvPFq1i_JTHbihSBrq4JisRZ6F77JQbOdk8lsZf59s56ohUAC7_O9JHkI-UJhRmnJDnE5BNthMwOgTM4YUPhAtlPCcloIsZHOktO8Kue_tshOjEtIIGX0I9liIAs-n8M2uWpvr28W9JBl2Jks4IDtpH2XpeVsi43NzrE7-vH95jSFY8we_XifDX0z6SmOXme_venslBkfLUb7iWw6bKL9_LLvkp_fvt4uzvPL67OLxcllrgtOx9wJEKKyhTOlcEZWhUQpZVlrVhuHzkkharQOwdZGaGDM1BpMRQVWNRM18F1y_Nw7rOrWGm27MWCjhuBbDJPq0av3Sefv1V3_R3FgnPF1wcFLQegfVjaOqvVR26bBzvarqCrGJHCAKpH7_5HLfhXStyeIyzlnJS0SxJ8hHfoYg3VvV6Gg1rLUqyz1JEutZaWpvX9f8Tbzaof_BcJzkwE</recordid><startdate>20110101</startdate><enddate>20110101</enddate><creator>Belibi, Franck</creator><creator>Ravichandran, Kameswaran</creator><creator>Zafar, Iram</creator><creator>He, Zhibin</creator><creator>Edelstein, Charles L</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20110101</creationdate><title>mTORC1/2 and rapamycin in female Han:SPRD rats with polycystic kidney disease</title><author>Belibi, Franck ; Ravichandran, Kameswaran ; Zafar, Iram ; He, Zhibin ; Edelstein, Charles L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c431t-f60668e4fd56fd9849a9995bc2bdfaff966baefa0ebd6c022dbc0d816a8b26b03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Caspase 3 - metabolism</topic><topic>Drugs</topic><topic>Female</topic><topic>Kidney diseases</topic><topic>Nephrology</topic><topic>Pharmacology</topic><topic>Phosphorylation</topic><topic>Polycystic Kidney, Autosomal Dominant - drug therapy</topic><topic>Polycystic Kidney, Autosomal Dominant - metabolism</topic><topic>Polycystic Kidney, Autosomal Dominant - pathology</topic><topic>Protein Kinase C-alpha - metabolism</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Rats</topic><topic>Ribosomal Protein S6 - metabolism</topic><topic>Rodents</topic><topic>Sex Characteristics</topic><topic>Sirolimus - metabolism</topic><topic>Sirolimus - therapeutic use</topic><topic>TOR Serine-Threonine Kinases - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Belibi, Franck</creatorcontrib><creatorcontrib>Ravichandran, Kameswaran</creatorcontrib><creatorcontrib>Zafar, Iram</creatorcontrib><creatorcontrib>He, Zhibin</creatorcontrib><creatorcontrib>Edelstein, Charles L</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><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>Belibi, Franck</au><au>Ravichandran, Kameswaran</au><au>Zafar, Iram</au><au>He, Zhibin</au><au>Edelstein, Charles L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>mTORC1/2 and rapamycin in female Han:SPRD rats with polycystic kidney disease</atitle><jtitle>American Journal of Physiology - Renal Physiology</jtitle><addtitle>Am J Physiol Renal Physiol</addtitle><date>2011-01-01</date><risdate>2011</risdate><volume>300</volume><issue>1</issue><spage>F236</spage><epage>F244</epage><pages>F236-F244</pages><issn>1931-857X</issn><issn>0363-6127</issn><eissn>1522-1466</eissn><abstract>Rapamycin slows disease progression in the male Han:SPRD (Cy/+) rat with polycystic kidney disease (PKD). The aim of this study was to determine the effect of rapamycin on PKD and the relative contributions of the proproliferative mammalian target of rapamycin complexes 1 and 2 (mTORC1 and mTORC2) in female Cy/+ rats. Female Cy/+ rats were treated with rapamycin from 4 to 12 wk of age. In vehicle-treated Cy/+ rats, kidney volume increased by 40% and cyst volume density (CVD) was 19%. Phosphorylated S6 (p-S6) ribosomal protein, a marker of mTORC1 activity, was increased in Cy/+ rats compared with normal littermate controls (+/+) and decreased by rapamycin. Despite activation of mTORC1 in female Cy/+ rats, rapamycin had no effect on kidney size, CVD, number of PCNA-positive cystic tubular cells, caspase-3 activity, or the number of terminal deoxynucleotidyl transferase dUTP-mediated nick-end label-positive apoptotic cells. To determine a reason for the lack of effect of rapamycin, we studied the mTORC2 signaling pathway. On immunoblot of kidney, phosphorylated (Ser473) Akt (p-Akt), a marker of mTORC2 activity, was increased in female Cy/+ rats treated with rapamycin. Phosphorylated (Ser657) PKCα, a substrate of mTORC2, was unaffected by rapamycin in females. In contrast, in male rats, where rapamycin significantly decreases PKD, p-Akt (Ser473) was decreased by rapamcyin. PKCα (Ser657) was increased in male Cy/+ rats but was unaffected by rapamycin. In summary, in female Cy/+ rats, rapamycin had no effect on PKD and proproliferative p-Akt (Ser473) activity was increased by rapamycin. There were differential effects of rapamycin on mTORC2 signaling in female vs. male Cy/+ rats.</abstract><cop>United States</cop><pub>American Physiological Society</pub><pmid>20943770</pmid><doi>10.1152/ajprenal.00129.2010</doi><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 1931-857X
ispartof American Journal of Physiology - Renal Physiology, 2011-01, Vol.300 (1), p.F236-F244
issn 1931-857X
0363-6127
1522-1466
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3023230
source MEDLINE; American Physiological Society; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection
subjects Animals
Apoptosis
Caspase 3 - metabolism
Drugs
Female
Kidney diseases
Nephrology
Pharmacology
Phosphorylation
Polycystic Kidney, Autosomal Dominant - drug therapy
Polycystic Kidney, Autosomal Dominant - metabolism
Polycystic Kidney, Autosomal Dominant - pathology
Protein Kinase C-alpha - metabolism
Proto-Oncogene Proteins c-akt - metabolism
Rats
Ribosomal Protein S6 - metabolism
Rodents
Sex Characteristics
Sirolimus - metabolism
Sirolimus - therapeutic use
TOR Serine-Threonine Kinases - metabolism
title mTORC1/2 and rapamycin in female Han:SPRD rats with polycystic kidney disease
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-30T02%3A26%3A33IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=mTORC1/2%20and%20rapamycin%20in%20female%20Han:SPRD%20rats%20with%20polycystic%20kidney%20disease&rft.jtitle=American%20Journal%20of%20Physiology%20-%20Renal%20Physiology&rft.au=Belibi,%20Franck&rft.date=2011-01-01&rft.volume=300&rft.issue=1&rft.spage=F236&rft.epage=F244&rft.pages=F236-F244&rft.issn=1931-857X&rft.eissn=1522-1466&rft_id=info:doi/10.1152/ajprenal.00129.2010&rft_dat=%3Cproquest_pubme%3E2238005181%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=839732514&rft_id=info:pmid/20943770&rfr_iscdi=true