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...
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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 |
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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> |
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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 |
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