Luminal ANG II is internalized as a complex with AT 1 R/AT 2 R heterodimers to target endoplasmic reticulum in LLC-PK 1 cells
ANG II has many biological effects in renal physiology, particularly in Ca handling in the regulation of fluid and solute reabsorption. It involves the systemic endocrine renin-angiotensin system (RAS), but tissue and intracrine ANG II are also known. We have shown that ANG II induces heterodimeriza...
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| Veröffentlicht in: | American journal of physiology. Renal physiology 2017-08, Vol.313 (2), p.F440-F449 |
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| container_title | American journal of physiology. Renal physiology |
| container_volume | 313 |
| creator | Ferrão, Fernanda M Cardoso, Luiza H D Drummond, Heather A Li, Xiao C Zhuo, Jia L Gomes, Dayene S Lara, Lucienne S Vieyra, Adalberto Lowe, Jennifer |
| description | ANG II has many biological effects in renal physiology, particularly in Ca
handling in the regulation of fluid and solute reabsorption. It involves the systemic endocrine renin-angiotensin system (RAS), but tissue and intracrine ANG II are also known. We have shown that ANG II induces heterodimerization of its AT
and AT
receptors (AT
R and AT
R) to stimulate sarco(endo)plasmic reticulum Ca
-ATPase (SERCA) activity. Thus, we investigated whether ANG II-AT
R/AT
R complex is formed and internalized, and also examined the intracellular localization of this complex to determine how its effect might be exerted on renal intracrine RAS. Living cell imaging of LLC-PK
cells, quantification of extracellular ANG II, and use of the receptor antagonists, losartan and PD123319, showed that ANG II is internalized with AT
R/AT
R heterodimers as a complex in a microtubule-dependent and clathrin-independent manner, since colchicine-but not Pitstop2-blocked this process. This result was confirmed by an increase of β-arrestin phosphorylation after ANG II treatment, clathrin-mediated endocytosis being dependent on dephosphorylation of β-arrestin. Internalized ANG II colocalized with an endoplasmic reticulum (ER) marker and increased levels of AT
R, AT
R, and PKCα in ER-enriched membrane fractions. This novel evidence suggests the internalization of an ANG II-AT
/AT
complex to target ER, where it might trigger intracellular Ca
responses. |
| doi_str_mv | 10.1152/ajprenal.00261.2016 |
| format | Article |
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handling in the regulation of fluid and solute reabsorption. It involves the systemic endocrine renin-angiotensin system (RAS), but tissue and intracrine ANG II are also known. We have shown that ANG II induces heterodimerization of its AT
and AT
receptors (AT
R and AT
R) to stimulate sarco(endo)plasmic reticulum Ca
-ATPase (SERCA) activity. Thus, we investigated whether ANG II-AT
R/AT
R complex is formed and internalized, and also examined the intracellular localization of this complex to determine how its effect might be exerted on renal intracrine RAS. Living cell imaging of LLC-PK
cells, quantification of extracellular ANG II, and use of the receptor antagonists, losartan and PD123319, showed that ANG II is internalized with AT
R/AT
R heterodimers as a complex in a microtubule-dependent and clathrin-independent manner, since colchicine-but not Pitstop2-blocked this process. This result was confirmed by an increase of β-arrestin phosphorylation after ANG II treatment, clathrin-mediated endocytosis being dependent on dephosphorylation of β-arrestin. Internalized ANG II colocalized with an endoplasmic reticulum (ER) marker and increased levels of AT
R, AT
R, and PKCα in ER-enriched membrane fractions. This novel evidence suggests the internalization of an ANG II-AT
/AT
complex to target ER, where it might trigger intracellular Ca
responses.</description><identifier>ISSN: 1931-857X</identifier><identifier>EISSN: 1522-1466</identifier><identifier>DOI: 10.1152/ajprenal.00261.2016</identifier><identifier>PMID: 28468964</identifier><language>eng</language><publisher>United States</publisher><subject>Angiotensin II - metabolism ; Angiotensin II Type 1 Receptor Blockers - pharmacology ; Angiotensin II Type 2 Receptor Blockers - pharmacology ; Animals ; beta-Arrestins - metabolism ; Calcium - metabolism ; Cell Membrane - drug effects ; Cell Membrane - metabolism ; Endocytosis - drug effects ; Endoplasmic Reticulum - drug effects ; Endoplasmic Reticulum - metabolism ; Kidney - drug effects ; Kidney - metabolism ; LLC-PK1 Cells ; Microtubules - metabolism ; Multiprotein Complexes ; Phosphorylation ; Protein Kinase C-alpha - metabolism ; Protein Transport ; Receptor, Angiotensin, Type 1 - drug effects ; Receptor, Angiotensin, Type 1 - metabolism ; Receptor, Angiotensin, Type 2 - drug effects ; Receptor, Angiotensin, Type 2 - metabolism ; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism ; Swine</subject><ispartof>American journal of physiology. Renal physiology, 2017-08, Vol.313 (2), p.F440-F449</ispartof><rights>Copyright © 2017 the American Physiological Society.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c1174-b6751993bf063776b492d69015cd1dc2f133b06a2e29f0d9db58b83770027adc3</citedby><cites>FETCH-LOGICAL-c1174-b6751993bf063776b492d69015cd1dc2f133b06a2e29f0d9db58b83770027adc3</cites><orcidid>0000-0001-7378-4561</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3037,27922,27923</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28468964$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ferrão, Fernanda M</creatorcontrib><creatorcontrib>Cardoso, Luiza H D</creatorcontrib><creatorcontrib>Drummond, Heather A</creatorcontrib><creatorcontrib>Li, Xiao C</creatorcontrib><creatorcontrib>Zhuo, Jia L</creatorcontrib><creatorcontrib>Gomes, Dayene S</creatorcontrib><creatorcontrib>Lara, Lucienne S</creatorcontrib><creatorcontrib>Vieyra, Adalberto</creatorcontrib><creatorcontrib>Lowe, Jennifer</creatorcontrib><title>Luminal ANG II is internalized as a complex with AT 1 R/AT 2 R heterodimers to target endoplasmic reticulum in LLC-PK 1 cells</title><title>American journal of physiology. Renal physiology</title><addtitle>Am J Physiol Renal Physiol</addtitle><description>ANG II has many biological effects in renal physiology, particularly in Ca
handling in the regulation of fluid and solute reabsorption. It involves the systemic endocrine renin-angiotensin system (RAS), but tissue and intracrine ANG II are also known. We have shown that ANG II induces heterodimerization of its AT
and AT
receptors (AT
R and AT
R) to stimulate sarco(endo)plasmic reticulum Ca
-ATPase (SERCA) activity. Thus, we investigated whether ANG II-AT
R/AT
R complex is formed and internalized, and also examined the intracellular localization of this complex to determine how its effect might be exerted on renal intracrine RAS. Living cell imaging of LLC-PK
cells, quantification of extracellular ANG II, and use of the receptor antagonists, losartan and PD123319, showed that ANG II is internalized with AT
R/AT
R heterodimers as a complex in a microtubule-dependent and clathrin-independent manner, since colchicine-but not Pitstop2-blocked this process. This result was confirmed by an increase of β-arrestin phosphorylation after ANG II treatment, clathrin-mediated endocytosis being dependent on dephosphorylation of β-arrestin. Internalized ANG II colocalized with an endoplasmic reticulum (ER) marker and increased levels of AT
R, AT
R, and PKCα in ER-enriched membrane fractions. This novel evidence suggests the internalization of an ANG II-AT
/AT
complex to target ER, where it might trigger intracellular Ca
responses.</description><subject>Angiotensin II - metabolism</subject><subject>Angiotensin II Type 1 Receptor Blockers - pharmacology</subject><subject>Angiotensin II Type 2 Receptor Blockers - pharmacology</subject><subject>Animals</subject><subject>beta-Arrestins - metabolism</subject><subject>Calcium - metabolism</subject><subject>Cell Membrane - drug effects</subject><subject>Cell Membrane - metabolism</subject><subject>Endocytosis - drug effects</subject><subject>Endoplasmic Reticulum - drug effects</subject><subject>Endoplasmic Reticulum - metabolism</subject><subject>Kidney - drug effects</subject><subject>Kidney - metabolism</subject><subject>LLC-PK1 Cells</subject><subject>Microtubules - metabolism</subject><subject>Multiprotein Complexes</subject><subject>Phosphorylation</subject><subject>Protein Kinase C-alpha - metabolism</subject><subject>Protein Transport</subject><subject>Receptor, Angiotensin, Type 1 - drug effects</subject><subject>Receptor, Angiotensin, Type 1 - metabolism</subject><subject>Receptor, Angiotensin, Type 2 - drug effects</subject><subject>Receptor, Angiotensin, Type 2 - metabolism</subject><subject>Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism</subject><subject>Swine</subject><issn>1931-857X</issn><issn>1522-1466</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kF1LwzAUhoMobk5_gSDnD3TLSdu0vRxD57CojAnelTRJXUa7lqTDD_C_mznn1Tmc877PxUPINdIxYswmYtNZvRX1mFLGccwo8hMy9B8WYMT5qd-zEIM0Tl4H5MK5DaUUkeE5GbA04mnGoyH5zneN8RCYPs5hsQDjwGx7bf3JfGkFwoEA2TZdrT_g3fRrmK4AYTnxg8ES1tqHW2UabR30LfTCvuke9Fa1XS1cYyRY3Ru5q3eNJ0Oez4LnB0-Quq7dJTmrRO301d8ckZe729XsPsif5ovZNA8kYhIFJU9izLKwrCgPk4SXUcYUzyjGUqGSrMIwLCkXTLOsoipTZZyWqU96M4lQMhyR8MCVtnXO6qrorGmE_SyQFnuZxVFm8Suz2Mv0rZtDq9uVjVb_naO98AfVAnBH</recordid><startdate>20170801</startdate><enddate>20170801</enddate><creator>Ferrão, Fernanda M</creator><creator>Cardoso, Luiza H D</creator><creator>Drummond, Heather A</creator><creator>Li, Xiao C</creator><creator>Zhuo, Jia L</creator><creator>Gomes, Dayene S</creator><creator>Lara, Lucienne S</creator><creator>Vieyra, Adalberto</creator><creator>Lowe, Jennifer</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><orcidid>https://orcid.org/0000-0001-7378-4561</orcidid></search><sort><creationdate>20170801</creationdate><title>Luminal ANG II is internalized as a complex with AT 1 R/AT 2 R heterodimers to target endoplasmic reticulum in LLC-PK 1 cells</title><author>Ferrão, Fernanda M ; Cardoso, Luiza H D ; Drummond, Heather A ; Li, Xiao C ; Zhuo, Jia L ; Gomes, Dayene S ; Lara, Lucienne S ; Vieyra, Adalberto ; Lowe, Jennifer</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1174-b6751993bf063776b492d69015cd1dc2f133b06a2e29f0d9db58b83770027adc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Angiotensin II - metabolism</topic><topic>Angiotensin II Type 1 Receptor Blockers - pharmacology</topic><topic>Angiotensin II Type 2 Receptor Blockers - pharmacology</topic><topic>Animals</topic><topic>beta-Arrestins - metabolism</topic><topic>Calcium - metabolism</topic><topic>Cell Membrane - drug effects</topic><topic>Cell Membrane - metabolism</topic><topic>Endocytosis - drug effects</topic><topic>Endoplasmic Reticulum - drug effects</topic><topic>Endoplasmic Reticulum - metabolism</topic><topic>Kidney - drug effects</topic><topic>Kidney - metabolism</topic><topic>LLC-PK1 Cells</topic><topic>Microtubules - metabolism</topic><topic>Multiprotein Complexes</topic><topic>Phosphorylation</topic><topic>Protein Kinase C-alpha - metabolism</topic><topic>Protein Transport</topic><topic>Receptor, Angiotensin, Type 1 - drug effects</topic><topic>Receptor, Angiotensin, Type 1 - metabolism</topic><topic>Receptor, Angiotensin, Type 2 - drug effects</topic><topic>Receptor, Angiotensin, Type 2 - metabolism</topic><topic>Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism</topic><topic>Swine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ferrão, Fernanda M</creatorcontrib><creatorcontrib>Cardoso, Luiza H D</creatorcontrib><creatorcontrib>Drummond, Heather A</creatorcontrib><creatorcontrib>Li, Xiao C</creatorcontrib><creatorcontrib>Zhuo, Jia L</creatorcontrib><creatorcontrib>Gomes, Dayene S</creatorcontrib><creatorcontrib>Lara, Lucienne S</creatorcontrib><creatorcontrib>Vieyra, Adalberto</creatorcontrib><creatorcontrib>Lowe, Jennifer</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>American journal of physiology. Renal physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ferrão, Fernanda M</au><au>Cardoso, Luiza H D</au><au>Drummond, Heather A</au><au>Li, Xiao C</au><au>Zhuo, Jia L</au><au>Gomes, Dayene S</au><au>Lara, Lucienne S</au><au>Vieyra, Adalberto</au><au>Lowe, Jennifer</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Luminal ANG II is internalized as a complex with AT 1 R/AT 2 R heterodimers to target endoplasmic reticulum in LLC-PK 1 cells</atitle><jtitle>American journal of physiology. Renal physiology</jtitle><addtitle>Am J Physiol Renal Physiol</addtitle><date>2017-08-01</date><risdate>2017</risdate><volume>313</volume><issue>2</issue><spage>F440</spage><epage>F449</epage><pages>F440-F449</pages><issn>1931-857X</issn><eissn>1522-1466</eissn><abstract>ANG II has many biological effects in renal physiology, particularly in Ca
handling in the regulation of fluid and solute reabsorption. It involves the systemic endocrine renin-angiotensin system (RAS), but tissue and intracrine ANG II are also known. We have shown that ANG II induces heterodimerization of its AT
and AT
receptors (AT
R and AT
R) to stimulate sarco(endo)plasmic reticulum Ca
-ATPase (SERCA) activity. Thus, we investigated whether ANG II-AT
R/AT
R complex is formed and internalized, and also examined the intracellular localization of this complex to determine how its effect might be exerted on renal intracrine RAS. Living cell imaging of LLC-PK
cells, quantification of extracellular ANG II, and use of the receptor antagonists, losartan and PD123319, showed that ANG II is internalized with AT
R/AT
R heterodimers as a complex in a microtubule-dependent and clathrin-independent manner, since colchicine-but not Pitstop2-blocked this process. This result was confirmed by an increase of β-arrestin phosphorylation after ANG II treatment, clathrin-mediated endocytosis being dependent on dephosphorylation of β-arrestin. Internalized ANG II colocalized with an endoplasmic reticulum (ER) marker and increased levels of AT
R, AT
R, and PKCα in ER-enriched membrane fractions. This novel evidence suggests the internalization of an ANG II-AT
/AT
complex to target ER, where it might trigger intracellular Ca
responses.</abstract><cop>United States</cop><pmid>28468964</pmid><doi>10.1152/ajprenal.00261.2016</doi><orcidid>https://orcid.org/0000-0001-7378-4561</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1931-857X |
| ispartof | American journal of physiology. Renal physiology, 2017-08, Vol.313 (2), p.F440-F449 |
| issn | 1931-857X 1522-1466 |
| language | eng |
| recordid | cdi_crossref_primary_10_1152_ajprenal_00261_2016 |
| source | MEDLINE; American Physiological Society; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Angiotensin II - metabolism Angiotensin II Type 1 Receptor Blockers - pharmacology Angiotensin II Type 2 Receptor Blockers - pharmacology Animals beta-Arrestins - metabolism Calcium - metabolism Cell Membrane - drug effects Cell Membrane - metabolism Endocytosis - drug effects Endoplasmic Reticulum - drug effects Endoplasmic Reticulum - metabolism Kidney - drug effects Kidney - metabolism LLC-PK1 Cells Microtubules - metabolism Multiprotein Complexes Phosphorylation Protein Kinase C-alpha - metabolism Protein Transport Receptor, Angiotensin, Type 1 - drug effects Receptor, Angiotensin, Type 1 - metabolism Receptor, Angiotensin, Type 2 - drug effects Receptor, Angiotensin, Type 2 - metabolism Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism Swine |
| title | Luminal ANG II is internalized as a complex with AT 1 R/AT 2 R heterodimers to target endoplasmic reticulum in LLC-PK 1 cells |
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