Renal Natriuretic Peptide Receptor-C Deficiency Attenuates NaCl Cotransporter Activity in Angiotensin II–Induced Hypertension
Genome-wide association studies have identified that NPR-C (natriuretic peptide receptor-C) variants are associated with elevation of blood pressure. However, the mechanism underlying the relationship between NPR-C and blood pressure regulation remains elusive. Here, we investigate whether NPR-C reg...
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Veröffentlicht in: | Hypertension (Dallas, Tex. 1979) Tex. 1979), 2021-03, Vol.77 (3), p.868-881 |
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creator | Shao, Shuai Li, Xiao-Dong Lu, Yuan-Yuan Li, Shi-Jin Chen, Xiao-Hui Zhou, Han-Dan He, Shun Guo, Yue-Tong Lu, Xiao Gao, Ping-Jin Wang, Ji-Guang |
description | Genome-wide association studies have identified that NPR-C (natriuretic peptide receptor-C) variants are associated with elevation of blood pressure. However, the mechanism underlying the relationship between NPR-C and blood pressure regulation remains elusive. Here, we investigate whether NPR-C regulates Ang II (angiotensin II)-induced hypertension through sodium transporters activity. Wild-type mice responded to continuous Ang II infusion with an increased renal NPR-C expression. Global NPR-C deficiency attenuated Ang II–induced increased blood pressure both in male and female mice associated with more diuretic and natriuretic responses to a saline challenge. Interestingly, Ang II increased both total and phosphorylation of NCC (NaCl cotransporter) abundance involving in activation of WNK4 (with-no-lysine kinase 4)/SPAK (Ste20-related proline/alanine-rich kinase) which was blunted by NPR-C deletion. NCC inhibitor, hydrochlorothiazide, failed to induce natriuresis in NPR-C knockout mice. Moreover, low-salt and high-salt diets–induced changes of total and phosphorylation of NCC expression were normalized by NPR-C deletion. Importantly, tubule-specific deletion of NPR-C also attenuated Ang II–induced elevated blood pressure, total and phosphorylation of NCC expression. Mechanistically, in distal convoluted tubule cells, Ang II dose and time-dependently upregulated WNK4/SPAK/NCC kinase pathway and NPR-C/Gi/PLC/PKC signaling pathway mediated NCC activation. These results demonstrate that NPR-C signaling regulates NCC function contributing to sodium retention-mediated elevated blood pressure, which suggests that NPR-C is a promising candidate for the treatment of sodium retention-related hypertension. |
doi_str_mv | 10.1161/HYPERTENSIONAHA.120.15636 |
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However, the mechanism underlying the relationship between NPR-C and blood pressure regulation remains elusive. Here, we investigate whether NPR-C regulates Ang II (angiotensin II)-induced hypertension through sodium transporters activity. Wild-type mice responded to continuous Ang II infusion with an increased renal NPR-C expression. Global NPR-C deficiency attenuated Ang II–induced increased blood pressure both in male and female mice associated with more diuretic and natriuretic responses to a saline challenge. Interestingly, Ang II increased both total and phosphorylation of NCC (NaCl cotransporter) abundance involving in activation of WNK4 (with-no-lysine kinase 4)/SPAK (Ste20-related proline/alanine-rich kinase) which was blunted by NPR-C deletion. NCC inhibitor, hydrochlorothiazide, failed to induce natriuresis in NPR-C knockout mice. Moreover, low-salt and high-salt diets–induced changes of total and phosphorylation of NCC expression were normalized by NPR-C deletion. Importantly, tubule-specific deletion of NPR-C also attenuated Ang II–induced elevated blood pressure, total and phosphorylation of NCC expression. Mechanistically, in distal convoluted tubule cells, Ang II dose and time-dependently upregulated WNK4/SPAK/NCC kinase pathway and NPR-C/Gi/PLC/PKC signaling pathway mediated NCC activation. These results demonstrate that NPR-C signaling regulates NCC function contributing to sodium retention-mediated elevated blood pressure, which suggests that NPR-C is a promising candidate for the treatment of sodium retention-related hypertension.</description><identifier>ISSN: 0194-911X</identifier><identifier>EISSN: 1524-4563</identifier><identifier>DOI: 10.1161/HYPERTENSIONAHA.120.15636</identifier><identifier>PMID: 33486984</identifier><language>eng</language><publisher>United States: American Heart Association, Inc</publisher><subject>Angiotensin II ; Animals ; Blood Pressure - genetics ; Blood Pressure - physiology ; Cells, Cultured ; Female ; Hypertension - chemically induced ; Hypertension - genetics ; Hypertension - physiopathology ; Kidney - metabolism ; Kidney Tubules, Distal - cytology ; Kidney Tubules, Distal - metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Protein Serine-Threonine Kinases - genetics ; Protein Serine-Threonine Kinases - metabolism ; Receptors, Atrial Natriuretic Factor - deficiency ; Receptors, Atrial Natriuretic Factor - genetics ; Renin-Angiotensin System - genetics ; Renin-Angiotensin System - physiology ; Signal Transduction - genetics ; Sodium - blood ; Sodium - urine ; Solute Carrier Family 12, Member 3 - genetics ; Solute Carrier Family 12, Member 3 - metabolism</subject><ispartof>Hypertension (Dallas, Tex. 1979), 2021-03, Vol.77 (3), p.868-881</ispartof><rights>American Heart Association, Inc</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5356-e14ad938600166f1766d42c89a3059a7bc08bf9fe9be4b0e5ca696e1f712f3b13</citedby><cites>FETCH-LOGICAL-c5356-e14ad938600166f1766d42c89a3059a7bc08bf9fe9be4b0e5ca696e1f712f3b13</cites><orcidid>0000-0002-3771-6286 ; 0000-0001-8511-1524</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3674,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33486984$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shao, Shuai</creatorcontrib><creatorcontrib>Li, Xiao-Dong</creatorcontrib><creatorcontrib>Lu, Yuan-Yuan</creatorcontrib><creatorcontrib>Li, Shi-Jin</creatorcontrib><creatorcontrib>Chen, Xiao-Hui</creatorcontrib><creatorcontrib>Zhou, Han-Dan</creatorcontrib><creatorcontrib>He, Shun</creatorcontrib><creatorcontrib>Guo, Yue-Tong</creatorcontrib><creatorcontrib>Lu, Xiao</creatorcontrib><creatorcontrib>Gao, Ping-Jin</creatorcontrib><creatorcontrib>Wang, Ji-Guang</creatorcontrib><title>Renal Natriuretic Peptide Receptor-C Deficiency Attenuates NaCl Cotransporter Activity in Angiotensin II–Induced Hypertension</title><title>Hypertension (Dallas, Tex. 1979)</title><addtitle>Hypertension</addtitle><description>Genome-wide association studies have identified that NPR-C (natriuretic peptide receptor-C) variants are associated with elevation of blood pressure. However, the mechanism underlying the relationship between NPR-C and blood pressure regulation remains elusive. Here, we investigate whether NPR-C regulates Ang II (angiotensin II)-induced hypertension through sodium transporters activity. Wild-type mice responded to continuous Ang II infusion with an increased renal NPR-C expression. Global NPR-C deficiency attenuated Ang II–induced increased blood pressure both in male and female mice associated with more diuretic and natriuretic responses to a saline challenge. Interestingly, Ang II increased both total and phosphorylation of NCC (NaCl cotransporter) abundance involving in activation of WNK4 (with-no-lysine kinase 4)/SPAK (Ste20-related proline/alanine-rich kinase) which was blunted by NPR-C deletion. NCC inhibitor, hydrochlorothiazide, failed to induce natriuresis in NPR-C knockout mice. Moreover, low-salt and high-salt diets–induced changes of total and phosphorylation of NCC expression were normalized by NPR-C deletion. Importantly, tubule-specific deletion of NPR-C also attenuated Ang II–induced elevated blood pressure, total and phosphorylation of NCC expression. Mechanistically, in distal convoluted tubule cells, Ang II dose and time-dependently upregulated WNK4/SPAK/NCC kinase pathway and NPR-C/Gi/PLC/PKC signaling pathway mediated NCC activation. These results demonstrate that NPR-C signaling regulates NCC function contributing to sodium retention-mediated elevated blood pressure, which suggests that NPR-C is a promising candidate for the treatment of sodium retention-related hypertension.</description><subject>Angiotensin II</subject><subject>Animals</subject><subject>Blood Pressure - genetics</subject><subject>Blood Pressure - physiology</subject><subject>Cells, Cultured</subject><subject>Female</subject><subject>Hypertension - chemically induced</subject><subject>Hypertension - genetics</subject><subject>Hypertension - physiopathology</subject><subject>Kidney - metabolism</subject><subject>Kidney Tubules, Distal - cytology</subject><subject>Kidney Tubules, Distal - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Mice, Transgenic</subject><subject>Protein Serine-Threonine Kinases - genetics</subject><subject>Protein Serine-Threonine Kinases - metabolism</subject><subject>Receptors, Atrial Natriuretic Factor - deficiency</subject><subject>Receptors, Atrial Natriuretic Factor - genetics</subject><subject>Renin-Angiotensin System - genetics</subject><subject>Renin-Angiotensin System - physiology</subject><subject>Signal Transduction - genetics</subject><subject>Sodium - blood</subject><subject>Sodium - urine</subject><subject>Solute Carrier Family 12, Member 3 - genetics</subject><subject>Solute Carrier Family 12, Member 3 - metabolism</subject><issn>0194-911X</issn><issn>1524-4563</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkMFO3DAQhi3UCra0r1CZBwh4YscbH6N0242EFrSlUnuKHGdSXEIS2U7Rnso79A15EgzbcmDmMDOa_x9pPkJOgJ0CSDhb_7hcba9Wm6_VxaZYF6eQxkUmuTwgC8hSkYg4vCELBkokCuD7EXnn_S_GQAixPCRHnItcqlwsyJ8tDrqnGx2cnR0Ga-glTsG2SLdoYje6pKSfsLPG4mB2tAgBh1kH9NFU9rQcg9ODn0YX0NHCBPvbhh21Ay2Gn3aMYh_7qnq4_1sN7WywpevdhO55MQ7vydtO9x4__KvH5Nvn1VW5Ts4vvlRlcZ6YjGcyQRC6VTyX8QcpO1hK2YrU5Epzlim9bAzLm051qBoUDcPMaKkkQreEtOMN8GOi9neNG7132NWTs7fa7Wpg9RPU-hXUOkKtn6FG78e9d5qbW2xfnP8pRoHYC-7GPlLwN_18h66-Rt2H65rFEKnMk5SlwHjMhD29wR8ByPSH_w</recordid><startdate>20210303</startdate><enddate>20210303</enddate><creator>Shao, Shuai</creator><creator>Li, Xiao-Dong</creator><creator>Lu, Yuan-Yuan</creator><creator>Li, Shi-Jin</creator><creator>Chen, Xiao-Hui</creator><creator>Zhou, Han-Dan</creator><creator>He, Shun</creator><creator>Guo, Yue-Tong</creator><creator>Lu, Xiao</creator><creator>Gao, Ping-Jin</creator><creator>Wang, Ji-Guang</creator><general>American Heart Association, Inc</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><orcidid>https://orcid.org/0000-0002-3771-6286</orcidid><orcidid>https://orcid.org/0000-0001-8511-1524</orcidid></search><sort><creationdate>20210303</creationdate><title>Renal Natriuretic Peptide Receptor-C Deficiency Attenuates NaCl Cotransporter Activity in Angiotensin II–Induced Hypertension</title><author>Shao, Shuai ; Li, Xiao-Dong ; Lu, Yuan-Yuan ; Li, Shi-Jin ; Chen, Xiao-Hui ; Zhou, Han-Dan ; He, Shun ; Guo, Yue-Tong ; Lu, Xiao ; Gao, Ping-Jin ; Wang, Ji-Guang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5356-e14ad938600166f1766d42c89a3059a7bc08bf9fe9be4b0e5ca696e1f712f3b13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Angiotensin II</topic><topic>Animals</topic><topic>Blood Pressure - genetics</topic><topic>Blood Pressure - physiology</topic><topic>Cells, Cultured</topic><topic>Female</topic><topic>Hypertension - chemically induced</topic><topic>Hypertension - genetics</topic><topic>Hypertension - physiopathology</topic><topic>Kidney - metabolism</topic><topic>Kidney Tubules, Distal - cytology</topic><topic>Kidney Tubules, Distal - metabolism</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Mice, Transgenic</topic><topic>Protein Serine-Threonine Kinases - genetics</topic><topic>Protein Serine-Threonine Kinases - metabolism</topic><topic>Receptors, Atrial Natriuretic Factor - deficiency</topic><topic>Receptors, Atrial Natriuretic Factor - genetics</topic><topic>Renin-Angiotensin System - genetics</topic><topic>Renin-Angiotensin System - physiology</topic><topic>Signal Transduction - genetics</topic><topic>Sodium - blood</topic><topic>Sodium - urine</topic><topic>Solute Carrier Family 12, Member 3 - genetics</topic><topic>Solute Carrier Family 12, Member 3 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shao, Shuai</creatorcontrib><creatorcontrib>Li, Xiao-Dong</creatorcontrib><creatorcontrib>Lu, Yuan-Yuan</creatorcontrib><creatorcontrib>Li, Shi-Jin</creatorcontrib><creatorcontrib>Chen, Xiao-Hui</creatorcontrib><creatorcontrib>Zhou, Han-Dan</creatorcontrib><creatorcontrib>He, Shun</creatorcontrib><creatorcontrib>Guo, Yue-Tong</creatorcontrib><creatorcontrib>Lu, Xiao</creatorcontrib><creatorcontrib>Gao, Ping-Jin</creatorcontrib><creatorcontrib>Wang, Ji-Guang</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Hypertension (Dallas, Tex. 1979)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shao, Shuai</au><au>Li, Xiao-Dong</au><au>Lu, Yuan-Yuan</au><au>Li, Shi-Jin</au><au>Chen, Xiao-Hui</au><au>Zhou, Han-Dan</au><au>He, Shun</au><au>Guo, Yue-Tong</au><au>Lu, Xiao</au><au>Gao, Ping-Jin</au><au>Wang, Ji-Guang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Renal Natriuretic Peptide Receptor-C Deficiency Attenuates NaCl Cotransporter Activity in Angiotensin II–Induced Hypertension</atitle><jtitle>Hypertension (Dallas, Tex. 1979)</jtitle><addtitle>Hypertension</addtitle><date>2021-03-03</date><risdate>2021</risdate><volume>77</volume><issue>3</issue><spage>868</spage><epage>881</epage><pages>868-881</pages><issn>0194-911X</issn><eissn>1524-4563</eissn><abstract>Genome-wide association studies have identified that NPR-C (natriuretic peptide receptor-C) variants are associated with elevation of blood pressure. However, the mechanism underlying the relationship between NPR-C and blood pressure regulation remains elusive. Here, we investigate whether NPR-C regulates Ang II (angiotensin II)-induced hypertension through sodium transporters activity. Wild-type mice responded to continuous Ang II infusion with an increased renal NPR-C expression. Global NPR-C deficiency attenuated Ang II–induced increased blood pressure both in male and female mice associated with more diuretic and natriuretic responses to a saline challenge. Interestingly, Ang II increased both total and phosphorylation of NCC (NaCl cotransporter) abundance involving in activation of WNK4 (with-no-lysine kinase 4)/SPAK (Ste20-related proline/alanine-rich kinase) which was blunted by NPR-C deletion. NCC inhibitor, hydrochlorothiazide, failed to induce natriuresis in NPR-C knockout mice. Moreover, low-salt and high-salt diets–induced changes of total and phosphorylation of NCC expression were normalized by NPR-C deletion. Importantly, tubule-specific deletion of NPR-C also attenuated Ang II–induced elevated blood pressure, total and phosphorylation of NCC expression. Mechanistically, in distal convoluted tubule cells, Ang II dose and time-dependently upregulated WNK4/SPAK/NCC kinase pathway and NPR-C/Gi/PLC/PKC signaling pathway mediated NCC activation. These results demonstrate that NPR-C signaling regulates NCC function contributing to sodium retention-mediated elevated blood pressure, which suggests that NPR-C is a promising candidate for the treatment of sodium retention-related hypertension.</abstract><cop>United States</cop><pub>American Heart Association, Inc</pub><pmid>33486984</pmid><doi>10.1161/HYPERTENSIONAHA.120.15636</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-3771-6286</orcidid><orcidid>https://orcid.org/0000-0001-8511-1524</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Angiotensin II Animals Blood Pressure - genetics Blood Pressure - physiology Cells, Cultured Female Hypertension - chemically induced Hypertension - genetics Hypertension - physiopathology Kidney - metabolism Kidney Tubules, Distal - cytology Kidney Tubules, Distal - metabolism Male Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Protein Serine-Threonine Kinases - genetics Protein Serine-Threonine Kinases - metabolism Receptors, Atrial Natriuretic Factor - deficiency Receptors, Atrial Natriuretic Factor - genetics Renin-Angiotensin System - genetics Renin-Angiotensin System - physiology Signal Transduction - genetics Sodium - blood Sodium - urine Solute Carrier Family 12, Member 3 - genetics Solute Carrier Family 12, Member 3 - metabolism |
title | Renal Natriuretic Peptide Receptor-C Deficiency Attenuates NaCl Cotransporter Activity in Angiotensin II–Induced Hypertension |
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