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Indoxyl Sulfate Downregulates Expression of Mas Receptor via OAT3/AhR/Stat3 Pathway in Proximal Tubular Cells

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) whic...

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Autores principales: Ng, Hwee-Yeong, Yisireyili, Maimaiti, Saito, Shinichi, Lee, Chien-Te, Adelibieke, Yelixiati, Nishijima, Fuyuhiko, Niwa, Toshimitsu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3948887/
https://www.ncbi.nlm.nih.gov/pubmed/24614509
http://dx.doi.org/10.1371/journal.pone.0091517
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author Ng, Hwee-Yeong
Yisireyili, Maimaiti
Saito, Shinichi
Lee, Chien-Te
Adelibieke, Yelixiati
Nishijima, Fuyuhiko
Niwa, Toshimitsu
author_facet Ng, Hwee-Yeong
Yisireyili, Maimaiti
Saito, Shinichi
Lee, Chien-Te
Adelibieke, Yelixiati
Nishijima, Fuyuhiko
Niwa, Toshimitsu
author_sort Ng, Hwee-Yeong
collection PubMed
description 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. CONCLUSION: 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.
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spelling pubmed-39488872014-03-13 Indoxyl Sulfate Downregulates Expression of Mas Receptor via OAT3/AhR/Stat3 Pathway in Proximal Tubular Cells Ng, Hwee-Yeong Yisireyili, Maimaiti Saito, Shinichi Lee, Chien-Te Adelibieke, Yelixiati Nishijima, Fuyuhiko Niwa, Toshimitsu PLoS One Research Article 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. CONCLUSION: 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. Public Library of Science 2014-03-10 /pmc/articles/PMC3948887/ /pubmed/24614509 http://dx.doi.org/10.1371/journal.pone.0091517 Text en © 2014 Ng et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Ng, Hwee-Yeong
Yisireyili, Maimaiti
Saito, Shinichi
Lee, Chien-Te
Adelibieke, Yelixiati
Nishijima, Fuyuhiko
Niwa, Toshimitsu
Indoxyl Sulfate Downregulates Expression of Mas Receptor via OAT3/AhR/Stat3 Pathway in Proximal Tubular Cells
title Indoxyl Sulfate Downregulates Expression of Mas Receptor via OAT3/AhR/Stat3 Pathway in Proximal Tubular Cells
title_full Indoxyl Sulfate Downregulates Expression of Mas Receptor via OAT3/AhR/Stat3 Pathway in Proximal Tubular Cells
title_fullStr Indoxyl Sulfate Downregulates Expression of Mas Receptor via OAT3/AhR/Stat3 Pathway in Proximal Tubular Cells
title_full_unstemmed Indoxyl Sulfate Downregulates Expression of Mas Receptor via OAT3/AhR/Stat3 Pathway in Proximal Tubular Cells
title_short Indoxyl Sulfate Downregulates Expression of Mas Receptor via OAT3/AhR/Stat3 Pathway in Proximal Tubular Cells
title_sort indoxyl sulfate downregulates expression of mas receptor via oat3/ahr/stat3 pathway in proximal tubular cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3948887/
https://www.ncbi.nlm.nih.gov/pubmed/24614509
http://dx.doi.org/10.1371/journal.pone.0091517
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