High glucose augments angiotensinogen in human renal proximal tubular cells through hepatocyte nuclear factor-5
High glucose has been demonstrated to induce angiotensinogen (AGT) synthesis in the renal proximal tubular cells (RPTCs) of rats, which may further activate the intrarenal renin-angiotensin system (RAS) and contribute to diabetic nephropathy. This study aimed to investigate the effects of high gluco...
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| description | High glucose has been demonstrated to induce angiotensinogen (AGT) synthesis in the renal proximal tubular cells (RPTCs) of rats, which may further activate the intrarenal renin-angiotensin system (RAS) and contribute to diabetic nephropathy. This study aimed to investigate the effects of high glucose on AGT in the RPTCs of human origin and identify the glucose-responsive transcriptional factor(s) that bind(s) to the DNA sequences of AGT promoter in human RPTCs. Human kidney (HK)-2 cells were treated with normal glucose (5.5 mM) and high glucose (15.0 mM), respectively. Levels of AGT mRNA and AGT secretion of HK-2 cells were measured by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Consecutive 5'-end deletion mutant constructs and different site-directed mutagenesis products of human AGT promoter sequences were respectively transfected into HK-2 cells, followed by AGT promoter activity measurement through dual luciferase assay. High glucose significantly augmented the levels of AGT mRNA and AGT secretion of HK-2 cells, compared with normal glucose treatment. High glucose also significantly augmented AGT promoter activity in HK-2 cells transfected with the constructs of human AGT promoter sequences, compared with normal glucose treatment. Hepatocyte nuclear factor (HNF)-5 was found to be one of the glucose-responsive transcriptional factors of AGT in human RPTCs, since the mutation of its binding sites within AGT promoter sequences abolished the above effects of high glucose on AGT promoter activity as well as levels of AGT mRNA and its secretion. The present study has demonstrated, for the first time, that high glucose augments AGT in human RPTCs through HNF-5, which provides a potential therapeutic target for diabetic nephropathy. |
| doi_str_mv | 10.1371/journal.pone.0185600 |
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This study aimed to investigate the effects of high glucose on AGT in the RPTCs of human origin and identify the glucose-responsive transcriptional factor(s) that bind(s) to the DNA sequences of AGT promoter in human RPTCs. Human kidney (HK)-2 cells were treated with normal glucose (5.5 mM) and high glucose (15.0 mM), respectively. Levels of AGT mRNA and AGT secretion of HK-2 cells were measured by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Consecutive 5'-end deletion mutant constructs and different site-directed mutagenesis products of human AGT promoter sequences were respectively transfected into HK-2 cells, followed by AGT promoter activity measurement through dual luciferase assay. High glucose significantly augmented the levels of AGT mRNA and AGT secretion of HK-2 cells, compared with normal glucose treatment. High glucose also significantly augmented AGT promoter activity in HK-2 cells transfected with the constructs of human AGT promoter sequences, compared with normal glucose treatment. Hepatocyte nuclear factor (HNF)-5 was found to be one of the glucose-responsive transcriptional factors of AGT in human RPTCs, since the mutation of its binding sites within AGT promoter sequences abolished the above effects of high glucose on AGT promoter activity as well as levels of AGT mRNA and its secretion. The present study has demonstrated, for the first time, that high glucose augments AGT in human RPTCs through HNF-5, which provides a potential therapeutic target for diabetic nephropathy.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0185600</identifier><identifier>PMID: 29053707</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Angiotensin ; Angiotensinogen ; Angiotensinogen - genetics ; Angiotensinogen - metabolism ; Animals ; Apoptosis ; Binding sites ; Biology and life sciences ; Biomarkers ; Cell Line ; Clonal deletion ; Construction sites ; Deletion mutant ; Deoxyribonucleic acid ; Diabetes ; Diabetes mellitus ; Diabetic nephropathy ; DNA ; Enzyme-Linked Immunosorbent Assay ; Forkhead Box Protein M1 - metabolism ; Gastroenterology ; Gene deletion ; Gene sequencing ; Glucose ; Glucose - administration & dosage ; Glucose - pharmacology ; Humans ; Kidney Tubules, Proximal - drug effects ; Kidney Tubules, Proximal - metabolism ; Medicine ; Medicine and Health Sciences ; Mutation ; Nephrology ; Nephropathy ; Nucleotide sequence ; Oxidative stress ; Pathogenesis ; Pharmacology ; Physical Sciences ; Physiology ; Polymerase chain reaction ; Promoter Regions, Genetic ; Rats ; Renin ; Research and Analysis Methods ; RNA, Messenger - genetics ; Rodents ; Site-directed mutagenesis ; Transcription factors ; Transcription Factors - metabolism</subject><ispartof>PloS one, 2017-10, Vol.12 (10), p.e0185600</ispartof><rights>2017 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2017 Wang et al 2017 Wang et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c676t-3a3faca8e7880924bccf3b79421c1ce80553fd83fb9d61a1d9fb845f2bf1e9bb3</citedby><cites>FETCH-LOGICAL-c676t-3a3faca8e7880924bccf3b79421c1ce80553fd83fb9d61a1d9fb845f2bf1e9bb3</cites><orcidid>0000-0001-5971-820X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650141/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650141/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29053707$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Abe, Hideharu</contributor><creatorcontrib>Wang, Juan</creatorcontrib><creatorcontrib>Shibayama, Yuki</creatorcontrib><creatorcontrib>Kobori, Hiroyuki</creatorcontrib><creatorcontrib>Liu, Ya</creatorcontrib><creatorcontrib>Kobara, Hideki</creatorcontrib><creatorcontrib>Masaki, Tsutomu</creatorcontrib><creatorcontrib>Wang, Zhiyu</creatorcontrib><creatorcontrib>Nishiyama, Akira</creatorcontrib><title>High glucose augments angiotensinogen in human renal proximal tubular cells through hepatocyte nuclear factor-5</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>High glucose has been demonstrated to induce angiotensinogen (AGT) synthesis in the renal proximal tubular cells (RPTCs) of rats, which may further activate the intrarenal renin-angiotensin system (RAS) and contribute to diabetic nephropathy. This study aimed to investigate the effects of high glucose on AGT in the RPTCs of human origin and identify the glucose-responsive transcriptional factor(s) that bind(s) to the DNA sequences of AGT promoter in human RPTCs. Human kidney (HK)-2 cells were treated with normal glucose (5.5 mM) and high glucose (15.0 mM), respectively. Levels of AGT mRNA and AGT secretion of HK-2 cells were measured by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Consecutive 5'-end deletion mutant constructs and different site-directed mutagenesis products of human AGT promoter sequences were respectively transfected into HK-2 cells, followed by AGT promoter activity measurement through dual luciferase assay. High glucose significantly augmented the levels of AGT mRNA and AGT secretion of HK-2 cells, compared with normal glucose treatment. High glucose also significantly augmented AGT promoter activity in HK-2 cells transfected with the constructs of human AGT promoter sequences, compared with normal glucose treatment. Hepatocyte nuclear factor (HNF)-5 was found to be one of the glucose-responsive transcriptional factors of AGT in human RPTCs, since the mutation of its binding sites within AGT promoter sequences abolished the above effects of high glucose on AGT promoter activity as well as levels of AGT mRNA and its secretion. The present study has demonstrated, for the first time, that high glucose augments AGT in human RPTCs through HNF-5, which provides a potential therapeutic target for diabetic nephropathy.</description><subject>Angiotensin</subject><subject>Angiotensinogen</subject><subject>Angiotensinogen - genetics</subject><subject>Angiotensinogen - metabolism</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Binding sites</subject><subject>Biology and life sciences</subject><subject>Biomarkers</subject><subject>Cell Line</subject><subject>Clonal deletion</subject><subject>Construction sites</subject><subject>Deletion mutant</subject><subject>Deoxyribonucleic acid</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetic nephropathy</subject><subject>DNA</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Forkhead Box Protein M1 - metabolism</subject><subject>Gastroenterology</subject><subject>Gene deletion</subject><subject>Gene sequencing</subject><subject>Glucose</subject><subject>Glucose - administration & dosage</subject><subject>Glucose - pharmacology</subject><subject>Humans</subject><subject>Kidney Tubules, Proximal - drug effects</subject><subject>Kidney Tubules, Proximal - metabolism</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Mutation</subject><subject>Nephrology</subject><subject>Nephropathy</subject><subject>Nucleotide sequence</subject><subject>Oxidative stress</subject><subject>Pathogenesis</subject><subject>Pharmacology</subject><subject>Physical Sciences</subject><subject>Physiology</subject><subject>Polymerase chain reaction</subject><subject>Promoter Regions, Genetic</subject><subject>Rats</subject><subject>Renin</subject><subject>Research and Analysis Methods</subject><subject>RNA, Messenger - genetics</subject><subject>Rodents</subject><subject>Site-directed mutagenesis</subject><subject>Transcription factors</subject><subject>Transcription Factors - metabolism</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNp1Ul1v1SAYbhaXbU7_gVESr3uEUii9MTGLuiVLvNFrAvSl7UkPVD6M-_eynW7ZLrziDTxfvHmq6h3BO0I78mnvc3Bq2a3ewQ4TwTjGJ9UF6WlT8wbTV8_m8-p1jHuMGRWcn1XnTV_GDncXlb-exwmNSzY-AlJ5PIBLESk3zj6Bi7PzIzg0OzTlg3IoQPFEa_B_50MZUtZ5UQEZWJaI0hR8LnITrCp5c5cAuWwWKACrTPKhZm-qU6uWCG-387L69e3rz6vr-vbH95urL7e14R1PNVW0MJSATgjcN602xlLd9W1DDDEgMGPUDoJa3Q-cKDL0VouW2UZbAr3W9LL6cNRdFx_ltqsoSc8oZbzp-oK4OSIGr_ZyDeU_4U56NcuHCx9GqUKaS3xJ2taIjlrMgLcWuOKCCNMIPKiSxQ5F6_PmlvUBBlN2GNTyQvTli5snOfo_knGGSUuKwMdNIPjfGWL6T-T2iDLBxxjAPjkQLO9L8ciS96WQWykK7f3zdE-kxxbQf-ycuUc</recordid><startdate>20171020</startdate><enddate>20171020</enddate><creator>Wang, Juan</creator><creator>Shibayama, Yuki</creator><creator>Kobori, Hiroyuki</creator><creator>Liu, Ya</creator><creator>Kobara, Hideki</creator><creator>Masaki, Tsutomu</creator><creator>Wang, Zhiyu</creator><creator>Nishiyama, Akira</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0001-5971-820X</orcidid></search><sort><creationdate>20171020</creationdate><title>High glucose augments angiotensinogen in human renal proximal tubular cells through hepatocyte nuclear factor-5</title><author>Wang, Juan ; Shibayama, Yuki ; Kobori, Hiroyuki ; Liu, Ya ; Kobara, Hideki ; Masaki, Tsutomu ; Wang, Zhiyu ; Nishiyama, Akira</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c676t-3a3faca8e7880924bccf3b79421c1ce80553fd83fb9d61a1d9fb845f2bf1e9bb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Angiotensin</topic><topic>Angiotensinogen</topic><topic>Angiotensinogen - genetics</topic><topic>Angiotensinogen - metabolism</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Binding sites</topic><topic>Biology and life sciences</topic><topic>Biomarkers</topic><topic>Cell Line</topic><topic>Clonal deletion</topic><topic>Construction sites</topic><topic>Deletion mutant</topic><topic>Deoxyribonucleic acid</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetic nephropathy</topic><topic>DNA</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>Forkhead Box Protein M1 - metabolism</topic><topic>Gastroenterology</topic><topic>Gene deletion</topic><topic>Gene sequencing</topic><topic>Glucose</topic><topic>Glucose - administration & dosage</topic><topic>Glucose - pharmacology</topic><topic>Humans</topic><topic>Kidney Tubules, Proximal - drug effects</topic><topic>Kidney Tubules, Proximal - metabolism</topic><topic>Medicine</topic><topic>Medicine and Health Sciences</topic><topic>Mutation</topic><topic>Nephrology</topic><topic>Nephropathy</topic><topic>Nucleotide sequence</topic><topic>Oxidative stress</topic><topic>Pathogenesis</topic><topic>Pharmacology</topic><topic>Physical Sciences</topic><topic>Physiology</topic><topic>Polymerase chain reaction</topic><topic>Promoter Regions, Genetic</topic><topic>Rats</topic><topic>Renin</topic><topic>Research and Analysis Methods</topic><topic>RNA, Messenger - 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This study aimed to investigate the effects of high glucose on AGT in the RPTCs of human origin and identify the glucose-responsive transcriptional factor(s) that bind(s) to the DNA sequences of AGT promoter in human RPTCs. Human kidney (HK)-2 cells were treated with normal glucose (5.5 mM) and high glucose (15.0 mM), respectively. Levels of AGT mRNA and AGT secretion of HK-2 cells were measured by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Consecutive 5'-end deletion mutant constructs and different site-directed mutagenesis products of human AGT promoter sequences were respectively transfected into HK-2 cells, followed by AGT promoter activity measurement through dual luciferase assay. High glucose significantly augmented the levels of AGT mRNA and AGT secretion of HK-2 cells, compared with normal glucose treatment. High glucose also significantly augmented AGT promoter activity in HK-2 cells transfected with the constructs of human AGT promoter sequences, compared with normal glucose treatment. Hepatocyte nuclear factor (HNF)-5 was found to be one of the glucose-responsive transcriptional factors of AGT in human RPTCs, since the mutation of its binding sites within AGT promoter sequences abolished the above effects of high glucose on AGT promoter activity as well as levels of AGT mRNA and its secretion. The present study has demonstrated, for the first time, that high glucose augments AGT in human RPTCs through HNF-5, which provides a potential therapeutic target for diabetic nephropathy.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>29053707</pmid><doi>10.1371/journal.pone.0185600</doi><orcidid>https://orcid.org/0000-0001-5971-820X</orcidid><oa>free_for_read</oa></addata></record> |
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| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Angiotensin Angiotensinogen Angiotensinogen - genetics Angiotensinogen - metabolism Animals Apoptosis Binding sites Biology and life sciences Biomarkers Cell Line Clonal deletion Construction sites Deletion mutant Deoxyribonucleic acid Diabetes Diabetes mellitus Diabetic nephropathy DNA Enzyme-Linked Immunosorbent Assay Forkhead Box Protein M1 - metabolism Gastroenterology Gene deletion Gene sequencing Glucose Glucose - administration & dosage Glucose - pharmacology Humans Kidney Tubules, Proximal - drug effects Kidney Tubules, Proximal - metabolism Medicine Medicine and Health Sciences Mutation Nephrology Nephropathy Nucleotide sequence Oxidative stress Pathogenesis Pharmacology Physical Sciences Physiology Polymerase chain reaction Promoter Regions, Genetic Rats Renin Research and Analysis Methods RNA, Messenger - genetics Rodents Site-directed mutagenesis Transcription factors Transcription Factors - metabolism |
| title | High glucose augments angiotensinogen in human renal proximal tubular cells through hepatocyte nuclear factor-5 |
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