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Indoxyl sulfate down-regulates SLCO4C1 transporter through up-regulation of GATA3
The accumulated uremic toxins inhibit the expression of various renal transporters and this inhibition may further reduce renal function and subsequently cause the accumulation of uremic toxins. However, the precise mechanism of the nephrotoxicity of uremic toxins on renal transport has been poorly...
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| Published in: | PloS one 2013-07, Vol.8 (7), p.e66518 |
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| creator | Akiyama, Yasutoshi Kikuchi, Koichi Saigusa, Daisuke Suzuki, Takehiro Takeuchi, Yoichi Mishima, Eikan Yamamoto, Yasuaki Ishida, Ayako Sugawara, Daiki Jinno, Daisuke Shima, Hisato Toyohara, Takafumi Suzuki, Chitose Souma, Tomokazu Moriguchi, Takashi Tomioka, Yoshihisa Ito, Sadayoshi Abe, Takaaki |
| description | The accumulated uremic toxins inhibit the expression of various renal transporters and this inhibition may further reduce renal function and subsequently cause the accumulation of uremic toxins. However, the precise mechanism of the nephrotoxicity of uremic toxins on renal transport has been poorly understood. Here we report that indoxyl sulfate, one of the potent uremic toxins, directly suppresses the renal-specific organic anion transporter SLCO4C1 expression through a transcription factor GATA3. The promoter region of SLCO4C1 gene has several GATA motifs, and indoxyl sulfate up-regulated GATA3 mRNA and subsequently down-regulated SLCO4C1 mRNA. Overexpression of GATA3 significantly reduced SLCO4C1 expression, and silencing of GATA3 increased SLCO4C1 expression vice versa. Administration of indoxyl sulfate in rats reduced renal expression of slco4c1 and under this condition, plasma level of guanidinosuccinate, one of the preferable substrates of slco4c1, was significantly increased without changing plasma creatinine. Furthermore, in 5/6 nephrectomized rats, treatment with oral adsorbent AST-120 significantly decreased plasma indoxyl sulfate level and conversely increased the expression of slco4c1, following the reduction of plasma level of guanidinosuccinate. These data suggest that the removal of indoxyl sulfate and blocking its signal pathway may help to restore the SLCO4C1-mediated renal excretion of uremic toxins in CKD. |
| doi_str_mv | 10.1371/journal.pone.0066518 |
| format | article |
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However, the precise mechanism of the nephrotoxicity of uremic toxins on renal transport has been poorly understood. Here we report that indoxyl sulfate, one of the potent uremic toxins, directly suppresses the renal-specific organic anion transporter SLCO4C1 expression through a transcription factor GATA3. The promoter region of SLCO4C1 gene has several GATA motifs, and indoxyl sulfate up-regulated GATA3 mRNA and subsequently down-regulated SLCO4C1 mRNA. Overexpression of GATA3 significantly reduced SLCO4C1 expression, and silencing of GATA3 increased SLCO4C1 expression vice versa. Administration of indoxyl sulfate in rats reduced renal expression of slco4c1 and under this condition, plasma level of guanidinosuccinate, one of the preferable substrates of slco4c1, was significantly increased without changing plasma creatinine. Furthermore, in 5/6 nephrectomized rats, treatment with oral adsorbent AST-120 significantly decreased plasma indoxyl sulfate level and conversely increased the expression of slco4c1, following the reduction of plasma level of guanidinosuccinate. These data suggest that the removal of indoxyl sulfate and blocking its signal pathway may help to restore the SLCO4C1-mediated renal excretion of uremic toxins in CKD.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0066518</identifier><identifier>PMID: 23874392</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Biological Transport ; Biology ; Carbon - administration & dosage ; Carbon - pharmacology ; Cell Line ; Creatinine ; Disease Models, Animal ; Down-Regulation - drug effects ; Endocrinology ; Excretion ; GATA-3 protein ; GATA3 Transcription Factor - genetics ; GATA3 Transcription Factor - metabolism ; Gene expression ; Gene Expression Regulation - drug effects ; Genes ; Health promotion ; Humans ; Indican - pharmacology ; Kidney diseases ; Kidney Failure, Chronic - genetics ; Kidney Failure, Chronic - metabolism ; Kidney Failure, Chronic - physiopathology ; Laboratories ; Medicine ; Nephrology ; Oncology ; Organic Anion Transporters - genetics ; Organic Anion Transporters - metabolism ; Oxidative stress ; Oxides - administration & dosage ; Oxides - pharmacology ; Pharmaceutical sciences ; Pharmacy ; Proteins ; Rats ; Renal function ; RNA ; Rodents ; Substrates ; Sulfates ; Toxins ; Toxins, Biological - pharmacology ; Transcription (Genetics) ; University graduates</subject><ispartof>PloS one, 2013-07, Vol.8 (7), p.e66518</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Akiyama et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (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>2013 Akiyama et al 2013 Akiyama et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-ebb75d70470e2978933d8c94eb9378c5998b2fbc9d91a184182f50fe7755e7543</citedby><cites>FETCH-LOGICAL-c758t-ebb75d70470e2978933d8c94eb9378c5998b2fbc9d91a184182f50fe7755e7543</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1974583909/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1974583909?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,25731,27901,27902,36989,44566,53766,53768,74869</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23874392$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Akiyama, Yasutoshi</creatorcontrib><creatorcontrib>Kikuchi, Koichi</creatorcontrib><creatorcontrib>Saigusa, Daisuke</creatorcontrib><creatorcontrib>Suzuki, Takehiro</creatorcontrib><creatorcontrib>Takeuchi, Yoichi</creatorcontrib><creatorcontrib>Mishima, Eikan</creatorcontrib><creatorcontrib>Yamamoto, Yasuaki</creatorcontrib><creatorcontrib>Ishida, Ayako</creatorcontrib><creatorcontrib>Sugawara, Daiki</creatorcontrib><creatorcontrib>Jinno, Daisuke</creatorcontrib><creatorcontrib>Shima, Hisato</creatorcontrib><creatorcontrib>Toyohara, Takafumi</creatorcontrib><creatorcontrib>Suzuki, Chitose</creatorcontrib><creatorcontrib>Souma, Tomokazu</creatorcontrib><creatorcontrib>Moriguchi, Takashi</creatorcontrib><creatorcontrib>Tomioka, Yoshihisa</creatorcontrib><creatorcontrib>Ito, Sadayoshi</creatorcontrib><creatorcontrib>Abe, Takaaki</creatorcontrib><title>Indoxyl sulfate down-regulates SLCO4C1 transporter through up-regulation of GATA3</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The accumulated uremic toxins inhibit the expression of various renal transporters and this inhibition may further reduce renal function and subsequently cause the accumulation of uremic toxins. However, the precise mechanism of the nephrotoxicity of uremic toxins on renal transport has been poorly understood. Here we report that indoxyl sulfate, one of the potent uremic toxins, directly suppresses the renal-specific organic anion transporter SLCO4C1 expression through a transcription factor GATA3. The promoter region of SLCO4C1 gene has several GATA motifs, and indoxyl sulfate up-regulated GATA3 mRNA and subsequently down-regulated SLCO4C1 mRNA. Overexpression of GATA3 significantly reduced SLCO4C1 expression, and silencing of GATA3 increased SLCO4C1 expression vice versa. Administration of indoxyl sulfate in rats reduced renal expression of slco4c1 and under this condition, plasma level of guanidinosuccinate, one of the preferable substrates of slco4c1, was significantly increased without changing plasma creatinine. Furthermore, in 5/6 nephrectomized rats, treatment with oral adsorbent AST-120 significantly decreased plasma indoxyl sulfate level and conversely increased the expression of slco4c1, following the reduction of plasma level of guanidinosuccinate. These data suggest that the removal of indoxyl sulfate and blocking its signal pathway may help to restore the SLCO4C1-mediated renal excretion of uremic toxins in CKD.</description><subject>Animals</subject><subject>Biological Transport</subject><subject>Biology</subject><subject>Carbon - administration & dosage</subject><subject>Carbon - pharmacology</subject><subject>Cell Line</subject><subject>Creatinine</subject><subject>Disease Models, Animal</subject><subject>Down-Regulation - drug effects</subject><subject>Endocrinology</subject><subject>Excretion</subject><subject>GATA-3 protein</subject><subject>GATA3 Transcription Factor - genetics</subject><subject>GATA3 Transcription Factor - metabolism</subject><subject>Gene expression</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Genes</subject><subject>Health promotion</subject><subject>Humans</subject><subject>Indican - pharmacology</subject><subject>Kidney diseases</subject><subject>Kidney Failure, Chronic - genetics</subject><subject>Kidney Failure, Chronic - metabolism</subject><subject>Kidney Failure, Chronic - physiopathology</subject><subject>Laboratories</subject><subject>Medicine</subject><subject>Nephrology</subject><subject>Oncology</subject><subject>Organic Anion Transporters - genetics</subject><subject>Organic Anion Transporters - metabolism</subject><subject>Oxidative stress</subject><subject>Oxides - administration & dosage</subject><subject>Oxides - pharmacology</subject><subject>Pharmaceutical sciences</subject><subject>Pharmacy</subject><subject>Proteins</subject><subject>Rats</subject><subject>Renal function</subject><subject>RNA</subject><subject>Rodents</subject><subject>Substrates</subject><subject>Sulfates</subject><subject>Toxins</subject><subject>Toxins, Biological - pharmacology</subject><subject>Transcription (Genetics)</subject><subject>University graduates</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl2L1DAUhoso7rr6D0QLguBFx3w2yY0wDLoODAy6q7chTZO2Q6epSau7_96M01mmoCC5yNdz3nN4eZPkJQQLiBl8v3Oj71S76F1nFgDkOYX8UXIJBUZZjgB-fHa-SJ6FsAOAYp7nT5MLhDkjWKDL5Mu6K93dfZuGsbVqMGnpfnWZN9XYxltIbzarLVnBdPCqC73zg_HpUHs3VnU69iewcV3qbHq9vF3i58kTq9pgXkz7VfLt08fb1edss71er5abTDPKh8wUBaMlA4QBgwTjAuOSa0FMITDjmgrBC2QLLUoBFeQEcmQpsIYxSg2jBF8lr4-6feuCnNwIEgpGKMcCiEisj0Tp1E72vtkrfy-dauSfB-crqfzQ6NbInJVIIGZ4LizRVhWKkBIRFlurQlAYtT5M3cZib0ptuuhIOxOd_3RNLSv3U2IGckpxFHgzCXj3YzRh-MfIE1WpOFXTWRfF9L4JWi4J45hyiFGkFn-h4irNvtExD7aJ77OCd7OCyAzmbqjUGIJc33z9f3b7fc6-PWNro9qhDq4dD4EIc5AcQe1dCN7YB-cgkIc4n9yQhzjLKc6x7NW56w9Fp_zi3wnt7no</recordid><startdate>20130709</startdate><enddate>20130709</enddate><creator>Akiyama, Yasutoshi</creator><creator>Kikuchi, Koichi</creator><creator>Saigusa, Daisuke</creator><creator>Suzuki, Takehiro</creator><creator>Takeuchi, Yoichi</creator><creator>Mishima, Eikan</creator><creator>Yamamoto, Yasuaki</creator><creator>Ishida, Ayako</creator><creator>Sugawara, Daiki</creator><creator>Jinno, Daisuke</creator><creator>Shima, Hisato</creator><creator>Toyohara, Takafumi</creator><creator>Suzuki, Chitose</creator><creator>Souma, Tomokazu</creator><creator>Moriguchi, Takashi</creator><creator>Tomioka, Yoshihisa</creator><creator>Ito, Sadayoshi</creator><creator>Abe, Takaaki</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>IOV</scope><scope>ISR</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></search><sort><creationdate>20130709</creationdate><title>Indoxyl sulfate down-regulates SLCO4C1 transporter through up-regulation of GATA3</title><author>Akiyama, Yasutoshi ; Kikuchi, Koichi ; Saigusa, Daisuke ; Suzuki, Takehiro ; Takeuchi, Yoichi ; Mishima, Eikan ; Yamamoto, Yasuaki ; Ishida, Ayako ; Sugawara, Daiki ; Jinno, Daisuke ; Shima, Hisato ; Toyohara, Takafumi ; Suzuki, Chitose ; Souma, Tomokazu ; Moriguchi, Takashi ; Tomioka, Yoshihisa ; Ito, Sadayoshi ; Abe, Takaaki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c758t-ebb75d70470e2978933d8c94eb9378c5998b2fbc9d91a184182f50fe7755e7543</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Biological Transport</topic><topic>Biology</topic><topic>Carbon - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>Biological Sciences</collection><collection>Agriculture Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest advanced technologies & aerospace journals</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content (ProQuest)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Akiyama, Yasutoshi</au><au>Kikuchi, Koichi</au><au>Saigusa, Daisuke</au><au>Suzuki, Takehiro</au><au>Takeuchi, Yoichi</au><au>Mishima, Eikan</au><au>Yamamoto, Yasuaki</au><au>Ishida, Ayako</au><au>Sugawara, Daiki</au><au>Jinno, Daisuke</au><au>Shima, Hisato</au><au>Toyohara, Takafumi</au><au>Suzuki, Chitose</au><au>Souma, Tomokazu</au><au>Moriguchi, Takashi</au><au>Tomioka, Yoshihisa</au><au>Ito, Sadayoshi</au><au>Abe, Takaaki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Indoxyl sulfate down-regulates SLCO4C1 transporter through up-regulation of GATA3</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-07-09</date><risdate>2013</risdate><volume>8</volume><issue>7</issue><spage>e66518</spage><pages>e66518-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The accumulated uremic toxins inhibit the expression of various renal transporters and this inhibition may further reduce renal function and subsequently cause the accumulation of uremic toxins. However, the precise mechanism of the nephrotoxicity of uremic toxins on renal transport has been poorly understood. Here we report that indoxyl sulfate, one of the potent uremic toxins, directly suppresses the renal-specific organic anion transporter SLCO4C1 expression through a transcription factor GATA3. The promoter region of SLCO4C1 gene has several GATA motifs, and indoxyl sulfate up-regulated GATA3 mRNA and subsequently down-regulated SLCO4C1 mRNA. Overexpression of GATA3 significantly reduced SLCO4C1 expression, and silencing of GATA3 increased SLCO4C1 expression vice versa. Administration of indoxyl sulfate in rats reduced renal expression of slco4c1 and under this condition, plasma level of guanidinosuccinate, one of the preferable substrates of slco4c1, was significantly increased without changing plasma creatinine. Furthermore, in 5/6 nephrectomized rats, treatment with oral adsorbent AST-120 significantly decreased plasma indoxyl sulfate level and conversely increased the expression of slco4c1, following the reduction of plasma level of guanidinosuccinate. These data suggest that the removal of indoxyl sulfate and blocking its signal pathway may help to restore the SLCO4C1-mediated renal excretion of uremic toxins in CKD.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23874392</pmid><doi>10.1371/journal.pone.0066518</doi><tpages>e66518</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2013-07, Vol.8 (7), p.e66518 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1974583909 |
| source | Publicly Available Content (ProQuest); PubMed Central |
| subjects | Animals Biological Transport Biology Carbon - administration & dosage Carbon - pharmacology Cell Line Creatinine Disease Models, Animal Down-Regulation - drug effects Endocrinology Excretion GATA-3 protein GATA3 Transcription Factor - genetics GATA3 Transcription Factor - metabolism Gene expression Gene Expression Regulation - drug effects Genes Health promotion Humans Indican - pharmacology Kidney diseases Kidney Failure, Chronic - genetics Kidney Failure, Chronic - metabolism Kidney Failure, Chronic - physiopathology Laboratories Medicine Nephrology Oncology Organic Anion Transporters - genetics Organic Anion Transporters - metabolism Oxidative stress Oxides - administration & dosage Oxides - pharmacology Pharmaceutical sciences Pharmacy Proteins Rats Renal function RNA Rodents Substrates Sulfates Toxins Toxins, Biological - pharmacology Transcription (Genetics) University graduates |
| title | Indoxyl sulfate down-regulates SLCO4C1 transporter through up-regulation of GATA3 |
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