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Involvement of Elf3 on Smad3 activation-dependent injuries in podocytes and excretion of urinary exosome in diabetic nephropathy

Diabetic nephropathy (DN) is among the most serious complications of diabetes mellitus, and often leads to end-stage renal disease ultimately requiring dialysis or renal transplantation. The loss of podocytes has been reported to have a role in the onset and progression of DN. Here, we addressed the...

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Autores principales: Sakurai, Akiko, Ono, Hiroyuki, Ochi, Arisa, Matsuura, Motokazu, Yoshimoto, Sakiya, Kishi, Seiji, Murakami, Taichi, Tominaga, Tatsuya, Nagai, Kojiro, Abe, Hideharu, Doi, Toshio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544199/
https://www.ncbi.nlm.nih.gov/pubmed/31150422
http://dx.doi.org/10.1371/journal.pone.0216788
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author Sakurai, Akiko
Ono, Hiroyuki
Ochi, Arisa
Matsuura, Motokazu
Yoshimoto, Sakiya
Kishi, Seiji
Murakami, Taichi
Tominaga, Tatsuya
Nagai, Kojiro
Abe, Hideharu
Doi, Toshio
author_facet Sakurai, Akiko
Ono, Hiroyuki
Ochi, Arisa
Matsuura, Motokazu
Yoshimoto, Sakiya
Kishi, Seiji
Murakami, Taichi
Tominaga, Tatsuya
Nagai, Kojiro
Abe, Hideharu
Doi, Toshio
author_sort Sakurai, Akiko
collection PubMed
description Diabetic nephropathy (DN) is among the most serious complications of diabetes mellitus, and often leads to end-stage renal disease ultimately requiring dialysis or renal transplantation. The loss of podocytes has been reported to have a role in the onset and progression of DN. Here, we addressed the activation mechanism of Smad3 signaling in podocytes. Expression of RII and activation of Smad3 were induced by AGE exposure (P<0.05). Reduction of the activation of RII-Smad3 signaling ameliorated podocyte injuries in Smad3-knockout diabetic mice. The bone morphogenetic protein 4 (BMP4) significantly regulated activation of RII-Smad3 signalings (P<0.05). Moreover, the epithelium-specific transcription factor, Elf3was induced by AGE stimulation and, subsequently, upregulated RII expression in cultured podocytes. Induction of Elf3 and activation of RII-Smad3 signaling, leading to a decrease in WT1 expression, were observed in podocytes in diabetic human kidneys. Moreover, AGE treatment induced the secretion of Elf3-containing exosomes from cultured podocytes, which was dependent on the activation of the TGF-β-Smad3 signaling pathway. In addition, exosomal Elf3 protein in urine could be measured only in urinary exosomes from patients with DN. The appearance of urinary exosomal Elf3 protein in patients with DN suggested the existence of irreversible injuries in podocytes. The rate of decline in the estimated Glomerular Filtration Rate (eGFR) after measurement of urinary exosomal Elf3 protein levels in patients with DN (R(2) = 0.7259) might be useful as an early non-invasive marker for podocyte injuries in DN.
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spelling pubmed-65441992019-06-17 Involvement of Elf3 on Smad3 activation-dependent injuries in podocytes and excretion of urinary exosome in diabetic nephropathy Sakurai, Akiko Ono, Hiroyuki Ochi, Arisa Matsuura, Motokazu Yoshimoto, Sakiya Kishi, Seiji Murakami, Taichi Tominaga, Tatsuya Nagai, Kojiro Abe, Hideharu Doi, Toshio PLoS One Research Article Diabetic nephropathy (DN) is among the most serious complications of diabetes mellitus, and often leads to end-stage renal disease ultimately requiring dialysis or renal transplantation. The loss of podocytes has been reported to have a role in the onset and progression of DN. Here, we addressed the activation mechanism of Smad3 signaling in podocytes. Expression of RII and activation of Smad3 were induced by AGE exposure (P<0.05). Reduction of the activation of RII-Smad3 signaling ameliorated podocyte injuries in Smad3-knockout diabetic mice. The bone morphogenetic protein 4 (BMP4) significantly regulated activation of RII-Smad3 signalings (P<0.05). Moreover, the epithelium-specific transcription factor, Elf3was induced by AGE stimulation and, subsequently, upregulated RII expression in cultured podocytes. Induction of Elf3 and activation of RII-Smad3 signaling, leading to a decrease in WT1 expression, were observed in podocytes in diabetic human kidneys. Moreover, AGE treatment induced the secretion of Elf3-containing exosomes from cultured podocytes, which was dependent on the activation of the TGF-β-Smad3 signaling pathway. In addition, exosomal Elf3 protein in urine could be measured only in urinary exosomes from patients with DN. The appearance of urinary exosomal Elf3 protein in patients with DN suggested the existence of irreversible injuries in podocytes. The rate of decline in the estimated Glomerular Filtration Rate (eGFR) after measurement of urinary exosomal Elf3 protein levels in patients with DN (R(2) = 0.7259) might be useful as an early non-invasive marker for podocyte injuries in DN. Public Library of Science 2019-05-31 /pmc/articles/PMC6544199/ /pubmed/31150422 http://dx.doi.org/10.1371/journal.pone.0216788 Text en © 2019 Sakurai 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 (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Sakurai, Akiko
Ono, Hiroyuki
Ochi, Arisa
Matsuura, Motokazu
Yoshimoto, Sakiya
Kishi, Seiji
Murakami, Taichi
Tominaga, Tatsuya
Nagai, Kojiro
Abe, Hideharu
Doi, Toshio
Involvement of Elf3 on Smad3 activation-dependent injuries in podocytes and excretion of urinary exosome in diabetic nephropathy
title Involvement of Elf3 on Smad3 activation-dependent injuries in podocytes and excretion of urinary exosome in diabetic nephropathy
title_full Involvement of Elf3 on Smad3 activation-dependent injuries in podocytes and excretion of urinary exosome in diabetic nephropathy
title_fullStr Involvement of Elf3 on Smad3 activation-dependent injuries in podocytes and excretion of urinary exosome in diabetic nephropathy
title_full_unstemmed Involvement of Elf3 on Smad3 activation-dependent injuries in podocytes and excretion of urinary exosome in diabetic nephropathy
title_short Involvement of Elf3 on Smad3 activation-dependent injuries in podocytes and excretion of urinary exosome in diabetic nephropathy
title_sort involvement of elf3 on smad3 activation-dependent injuries in podocytes and excretion of urinary exosome in diabetic nephropathy
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544199/
https://www.ncbi.nlm.nih.gov/pubmed/31150422
http://dx.doi.org/10.1371/journal.pone.0216788
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