Indoxyl Sulfate Downregulates Expression of Mas Receptor via OAT3/AhR/Stat3 Pathway in Proximal Tubular Cells
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{"title"=>"Indoxyl sulfate downregulates expression of mas receptor via OAT3/AhR/stat3 pathway in proximal tubular cells", "type"=>"journal", "authors"=>[{"first_name"=>"Hwee Yeong", "last_name"=>"Ng", "scopus_author_id"=>"23482249400"}, {"first_name"=>"Maimaiti", "last_name"=>"Yisireyili", "scopus_author_id"=>"55331850500"}, {"first_name"=>"Shinichi", "last_name"=>"Saito", "scopus_author_id"=>"56229257400"}, {"first_name"=>"Chien Te", "last_name"=>"Lee", "scopus_author_id"=>"8308149100"}, {"first_name"=>"Yelixiati", "last_name"=>"Adelibieke", "scopus_author_id"=>"37010697400"}, {"first_name"=>"Fuyuhiko", "last_name"=>"Nishijima", "scopus_author_id"=>"24335600200"}, {"first_name"=>"Toshimitsu", "last_name"=>"Niwa", "scopus_author_id"=>"7201351258"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-84897493761", "pmid"=>"24614509", "sgr"=>"84897493761", "doi"=>"10.1371/journal.pone.0091517", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "issn"=>"19326203", "pui"=>"372755321"}, "id"=>"105db8bb-a469-3a0f-bf75-4692a7838de8", "abstract"=>"UNLABELLED: Renin-angiotensin system (RAS) plays a pivotal role in chronic kidney disease (CKD). Angiotensin converting enzyme-related carboxypeptidase 2 (ACE2)/angiotensin (Ang)-(1-7)/Mas receptor axis counteracts the deleterious actions of Ang II. ACE2 exerts its actions by cleaving Ang II into Ang-(1-7) which activates Mas receptor. This study aimed to determine if the expression of Mas receptor is altered in the kidneys of CKD rats, and if indoxyl sulfate (IS), a uremic toxin, affects the expression of Mas receptor in rat kidneys and cultured human proximal tubular cells (HK-2 cells). The expression of Mas receptor was examined in the kidneys of CKD and AST-120-treated CKD rats using immunohistochemistry. Further, the effects of IS on Mas receptor expression in the kidneys of normotensive and hypertensive rats were examined. The effects of IS on the expression of Mas receptor and phosphorylation of endothelial nitric oxide synthase (eNOS) in HK-2 cells were examined using immunoblotting. CKD rats showed reduced renal expression of Mas receptor, while AST-120 restored its expression. Administration of IS downregulated Mas receptor expression in the kidneys of normotensive and hypertensive rats. IS downregulated Mas receptor expression in HK-2 cells in a time- and dose-dependent manner. Knockdown of organic anion transporter 3 (OAT3), aryl hydrocarbon receptor (AhR), and signal transducer and activator of transcription 3 (Stat3) inhibited IS-induced downregulation of Mas receptor and phosphorylated eNOS. N-acetylcysteine, an antioxidant, also inhibited IS-induced downregulation of Mas receptor and phosphorylated eNOS. Ang-(1-7) attenuated IS-induced transforming growth factor-β1 (TGF-β1) expression.\\n\\nCONCLUSION: Mas receptor expression is reduced in the kidneys of CKD rats. IS downregulates renal expression of Mas receptor via OAT3/AhR/Stat3 pathway in proximal tubular cells. IS-induced downregulation of Mas receptor might be involved in upregulation of TGF-β1 in proximal tubular cells.", "link"=>"http://www.mendeley.com/research/indoxyl-sulfate-downregulates-expression-mas-receptor-via-oat3ahrstat3-pathway-proximal-tubular-cell", "reader_count"=>13, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Researcher"=>2, "Student > Ph. D. Student"=>2, "Student > Postgraduate"=>1, "Other"=>1, "Student > Master"=>1, "Student > Bachelor"=>3, "Lecturer"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Researcher"=>2, "Student > Ph. D. Student"=>2, "Student > Postgraduate"=>1, "Other"=>1, "Student > Master"=>1, "Student > Bachelor"=>3, "Lecturer"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Medicine and Dentistry"=>5, "Agricultural and Biological Sciences"=>4, "Pharmacology, Toxicology and Pharmaceutical Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>5}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>4}, "Unspecified"=>{"Unspecified"=>3}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Brazil"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1414526"], "description"=>"<p>HK-2 cells were treated with or without AhR siRNA (siAhR, 30 nM) (A). Knockdown of AhR inhibited IS-induced downregulation of Mas receptor (B) and peNOS (C) expression. Data are means±SE, expressed as relative change in comparison with the basal value (n<i>≥3</i> for every experiment). *p<0.05 <i>vs.</i> control; <b>#</b>p<0.05 <i>vs.</i> IS.</p>", "links"=>[], "tags"=>["genetics", "Human genetics", "Model organisms", "Animal models", "rat", "Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "STAT signaling family", "Signaling cascades", "Endocrinology", "Nephrology", "Chronic kidney disease", "dialysis", "ahr", "sirna", "mas", "receptor", "penos", "hk-2"], "article_id"=>957481, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Hwee-Yeong Ng", "Maimaiti Yisireyili", "Shinichi Saito", "Chien-Te Lee", "Yelixiati Adelibieke", "Fuyuhiko Nishijima", "Toshimitsu Niwa"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0091517.g004", "stats"=>{"downloads"=>0, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_AhR_siRNA_on_Mas_receptor_and_peNOS_expression_in_HK_2_cells_/957481", "title"=>"Effects of AhR siRNA on Mas receptor and peNOS expression in HK-2 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-03-10 04:02:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/1414525"], "description"=>"<p>HK-2 cells were treated with or without OAT3 siRNA (siOAT3, 10 nM) (A). Mas receptor (B) and peNOS (C) protein expression was abolished by knocking down OAT3. Data are means±SE, expressed as relative change in comparison with the basal value (n<i>≥3</i> for every experiment). *p<0.05 <i>vs.</i> control; <b>#</b>p<0.05 <i>vs.</i> IS.</p>", "links"=>[], "tags"=>["genetics", "Human genetics", "Model organisms", "Animal models", "rat", "Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "STAT signaling family", "Signaling cascades", "Endocrinology", "Nephrology", "Chronic kidney disease", "dialysis", "oat3", "sirna", "mas", "receptor", "penos", "hk-2"], "article_id"=>957480, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Hwee-Yeong Ng", "Maimaiti Yisireyili", "Shinichi Saito", "Chien-Te Lee", "Yelixiati Adelibieke", "Fuyuhiko Nishijima", "Toshimitsu Niwa"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0091517.g003", "stats"=>{"downloads"=>0, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_OAT3_siRNA_on_Mas_receptor_and_peNOS_expression_in_HK_2_cells_/957480", "title"=>"Effects of OAT3 siRNA on Mas receptor and peNOS expression in HK-2 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-03-10 04:02:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/1414534"], "description"=>"<p>IS accumulates in HK-2 cells via OAT3. In the cells, IS acts as a ligand of AhR. The IS-AhR complex then interacts with Stat3. In turn, Mas receptor is downregulated by IS-AhR-Stat3 or IS-AhR complex. This figure was created using Servier Medical Art (<a href=\"http://www.servier.com\" target=\"_blank\">www.servier.com</a>).</p>", "links"=>[], "tags"=>["genetics", "Human genetics", "Model organisms", "Animal models", "rat", "Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "STAT signaling family", "Signaling cascades", "Endocrinology", "Nephrology", "Chronic kidney disease", "dialysis", "is-induced", "mas", "receptor"], "article_id"=>957489, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Hwee-Yeong Ng", "Maimaiti Yisireyili", "Shinichi Saito", "Chien-Te Lee", "Yelixiati Adelibieke", "Fuyuhiko Nishijima", "Toshimitsu Niwa"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0091517.g008", "stats"=>{"downloads"=>0, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Schema_of_mechanism_of_IS_induced_Mas_receptor_downregulation_/957489", "title"=>"Schema of mechanism of IS-induced Mas receptor downregulation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-03-10 04:02:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/1414532"], "description"=>"<p>NAC (5 mM) inhibited IS-induced downregulation of Mas receptor (A) and peNOS (B) expression. Data are means±SE, expressed as relative change in comparison with the basal value (n<i>≥3</i> for every experiment). *p<0.05 <i>vs.</i> control; #p<0.05 <i>vs.</i> IS.</p>", "links"=>[], "tags"=>["genetics", "Human genetics", "Model organisms", "Animal models", "rat", "Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "STAT signaling family", "Signaling cascades", "Endocrinology", "Nephrology", "Chronic kidney disease", "dialysis", "nac", "mas", "receptor", "penos", "hk-2"], "article_id"=>957487, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Hwee-Yeong Ng", "Maimaiti Yisireyili", "Shinichi Saito", "Chien-Te Lee", "Yelixiati Adelibieke", "Fuyuhiko Nishijima", "Toshimitsu Niwa"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0091517.g006", "stats"=>{"downloads"=>0, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_NAC_on_Mas_receptor_and_peNOS_expression_in_HK_2_cells_/957487", "title"=>"Effects of NAC on Mas receptor and peNOS expression in HK-2 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-03-10 04:02:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/1414533"], "description"=>"<p>IS enhanced the expression of TGF-β1, whereas Ang-(1–7) inhibited it. Data are means±SE, expressed as relative change in comparison with the basal value (n<i>≥3</i> for every experiment). *p<0.05 <i>vs.</i> control; #p<0.05 <i>vs.</i> IS.</p>", "links"=>[], "tags"=>["genetics", "Human genetics", "Model organisms", "Animal models", "rat", "Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "STAT signaling family", "Signaling cascades", "Endocrinology", "Nephrology", "Chronic kidney disease", "dialysis", "is-treated", "hk2"], "article_id"=>957488, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Hwee-Yeong Ng", "Maimaiti Yisireyili", "Shinichi Saito", "Chien-Te Lee", "Yelixiati Adelibieke", "Fuyuhiko Nishijima", "Toshimitsu Niwa"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0091517.g007", "stats"=>{"downloads"=>5, "page_views"=>25, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_Ang_1_8211_7_on_TGF_946_1_expression_in_IS_treated_HK2_cells_/957488", "title"=>"Effect of Ang-(1–7) on TGF-β1 expression in IS-treated HK2 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-03-10 04:02:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/1414528"], "description"=>"<p>HK-2 cells were treated with or without Stat3 siRNA (siStat3, 10 nM) (A). Knockdown of Stat3 inhibited IS-induced downregulation of Mas receptor (B) and peNOS (C) expression. Data are means±SE, expressed as relative change in comparison with the basal value (n<i>≥3</i> for every experiment). *p<0.05 <i>vs.</i> control; #p<0.05 <i>vs.</i> IS.</p>", "links"=>[], "tags"=>["genetics", "Human genetics", "Model organisms", "Animal models", "rat", "Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "STAT signaling family", "Signaling cascades", "Endocrinology", "Nephrology", "Chronic kidney disease", "dialysis", "stat3", "sirna", "mas", "receptor", "penos", "hk-2"], "article_id"=>957483, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Hwee-Yeong Ng", "Maimaiti Yisireyili", "Shinichi Saito", "Chien-Te Lee", "Yelixiati Adelibieke", "Fuyuhiko Nishijima", "Toshimitsu Niwa"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0091517.g005", "stats"=>{"downloads"=>3, "page_views"=>29, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_Stat3_siRNA_on_Mas_receptor_and_peNOS_expression_in_HK_2_cells_/957483", "title"=>"Effects of Stat3 siRNA on Mas receptor and peNOS expression in HK-2 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-03-10 04:02:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/1414522"], "description"=>"<p>Mas receptor in the HK-2 was reduced by IS in a time- (A) and dose- (B) dependent manner. Bars represent means±SE, expressed as relative change in comparison with the basal value (n<i>≥3</i> for every experiment).*p<0.05 <i>vs.</i> basal value; **p<0.001 <i>vs.</i> basal value.</p>", "links"=>[], "tags"=>["genetics", "Human genetics", "Model organisms", "Animal models", "rat", "Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "STAT signaling family", "Signaling cascades", "Endocrinology", "Nephrology", "Chronic kidney disease", "dialysis", "dose-dependent", "mas", "receptor", "hk-2"], "article_id"=>957477, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Hwee-Yeong Ng", "Maimaiti Yisireyili", "Shinichi Saito", "Chien-Te Lee", "Yelixiati Adelibieke", "Fuyuhiko Nishijima", "Toshimitsu Niwa"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0091517.g002", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Time_and_dose_dependent_effects_of_IS_on_Mas_receptor_protein_expression_in_HK_2_cells_/957477", "title"=>"Time- and dose-dependent effects of IS on Mas receptor protein expression in HK-2 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-03-10 04:02:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/1414521"], "description"=>"<p>CKD rats showed significantly lower level of Mas receptor expression than normal. By administrating AST-120, Mas receptor expression was restored (A). The expression of Mas receptor was downregulated by IS in normotensive and hypertensive Dahl rats with normal renal function (B). The pictures were taken under ×400 magnification (n = 8 for each group). Data are expressed as mean±SE. ¶p<0.05 <i>vs.</i> normal; ψp<0.05 <i>vs.</i> CKD; *p<0.05 <i>vs.</i> DN; #p<0.05 <i>vs.</i> DH.</p>", "links"=>[], "tags"=>["genetics", "Human genetics", "Model organisms", "Animal models", "rat", "Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "STAT signaling family", "Signaling cascades", "Endocrinology", "Nephrology", "Chronic kidney disease", "dialysis", "staining", "mas", "receptor", "kidneys", "ckd", "dahl"], "article_id"=>957476, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Hwee-Yeong Ng", "Maimaiti Yisireyili", "Shinichi Saito", "Chien-Te Lee", "Yelixiati Adelibieke", "Fuyuhiko Nishijima", "Toshimitsu Niwa"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0091517.g001", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Immunohistochemical_staining_of_Mas_receptor_in_kidneys_of_CKD_and_Dahl_rats_/957476", "title"=>"Immunohistochemical staining of Mas receptor in kidneys of CKD and Dahl rats.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-03-10 04:02:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/1414535"], "description"=>"<p>Data were cited from reference <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0091517#pone.0091517-Bolati1\" target=\"_blank\">[11]</a> for animal study 1 and <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0091517#pone.0091517-Adijiang1\" target=\"_blank\">[12]</a> for animal study 2.</p><p>Data are expressed as mean±SE.</p><p>Abbreviation: CKD, chronic kidney disease; DN, Dahl normotensive rats; DH, Dahl hypertensive rats; IS, indoxyl sulfate.</p>¶<p>p<0.05 <i>vs</i>. normal, <sup>ψ</sup>p<0.05 <i>vs</i>. CKD.</p><p>*p<0.05 <i>vs.</i> DN, <sup>#</sup>p<0.05 <i>vs.</i> DH.</p>", "links"=>[], "tags"=>["genetics", "Human genetics", "Model organisms", "Animal models", "rat", "Molecular cell biology", "Signal transduction", "Signaling in cellular processes", "STAT signaling family", "Signaling cascades", "Endocrinology", "Nephrology", "Chronic kidney disease", "dialysis", "animals"], "article_id"=>957490, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Hwee-Yeong Ng", "Maimaiti Yisireyili", "Shinichi Saito", "Chien-Te Lee", "Yelixiati Adelibieke", "Fuyuhiko Nishijima", "Toshimitsu Niwa"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0091517.t001", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Biochemical_data_of_the_animals_at_the_end_of_the_study_/957490", "title"=>"Biochemical data of the animals at the end of the study.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-03-10 04:02:03"}

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