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An adjustment in BMP4 function represents a treatment for diabetic nephropathy and podocyte injury

Podocyte injury has been proposed to play an important role in diabetic nephropathy; however, its pathological mechanism remains unclear. We have shown that bone morphogenetic protein 4 (BMP4) signaling leads to the glomerular changes characteristic of this disorder. To analyze the molecular mechani...

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Autores principales: Fujita, Yui, Tominaga, Tatsuya, Abe, Hideharu, Kangawa, Yumi, Fukushima, Naoshi, Ueda, Otoya, Jishage, Kou-ichi, Kishi, Seiji, Murakami, Taichi, Saga, Yumiko, Kanwar, Yashpal S., Nagai, Kojiro, Doi, Toshio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115362/
https://www.ncbi.nlm.nih.gov/pubmed/30158674
http://dx.doi.org/10.1038/s41598-018-31464-9
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author Fujita, Yui
Tominaga, Tatsuya
Abe, Hideharu
Kangawa, Yumi
Fukushima, Naoshi
Ueda, Otoya
Jishage, Kou-ichi
Kishi, Seiji
Murakami, Taichi
Saga, Yumiko
Kanwar, Yashpal S.
Nagai, Kojiro
Doi, Toshio
author_facet Fujita, Yui
Tominaga, Tatsuya
Abe, Hideharu
Kangawa, Yumi
Fukushima, Naoshi
Ueda, Otoya
Jishage, Kou-ichi
Kishi, Seiji
Murakami, Taichi
Saga, Yumiko
Kanwar, Yashpal S.
Nagai, Kojiro
Doi, Toshio
author_sort Fujita, Yui
collection PubMed
description Podocyte injury has been proposed to play an important role in diabetic nephropathy; however, its pathological mechanism remains unclear. We have shown that bone morphogenetic protein 4 (BMP4) signaling leads to the glomerular changes characteristic of this disorder. To analyze the molecular mechanism of podocyte injury, the effect of BMP4 was investigated using streptozotocin (STZ)-induced, Bmp4 heterozygous knockout (Bmp4+/−) and podocyte-specific Bmp4 knockout mice. Mice with STZ-induced diabetes exhibited glomerular matrix hyperplasia and decreased numbers of podocyte nucleus-specific WT1-positive cells. The number of podocytes and proteinuria were improved in both diabetic Bmp4 knockout mouse models compared to the effects observed in the control mice. The effect of BMP4 overexpression on Bmp4-induced or podocyte-specific transgenic mice was examined. Tamoxifen-induced Bmp4-overexpressing mice exhibited mesangial matrix expansion and decreased numbers of WT1-positive cells. Podocyte-specific Bmp4-overexpressing mice displayed increased kidney BMP4 expression and mesangial matrix expansion but decreased nephrin expression and numbers of WT1-positive cells. Both lines of Bmp4-overexpressing mice exhibited increased albuminuria. In cultured podocytes, BMP4 increased phospho-p38 levels. BMP4 decreased nephrin expression but increased cleaved caspase-3 levels. p38 suppression inhibited caspase-3 activation. Apoptosis was confirmed in STZ-diabetic glomeruli and Bmp4-overexpressing mice. Bmp4 +/− mice with diabetes displayed reduced apoptosis. Based on these data, the BMP4 signaling pathway plays important roles in the development of both podocyte injury and mesangial matrix expansion in diabetic nephropathy.
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spelling pubmed-61153622018-09-04 An adjustment in BMP4 function represents a treatment for diabetic nephropathy and podocyte injury Fujita, Yui Tominaga, Tatsuya Abe, Hideharu Kangawa, Yumi Fukushima, Naoshi Ueda, Otoya Jishage, Kou-ichi Kishi, Seiji Murakami, Taichi Saga, Yumiko Kanwar, Yashpal S. Nagai, Kojiro Doi, Toshio Sci Rep Article Podocyte injury has been proposed to play an important role in diabetic nephropathy; however, its pathological mechanism remains unclear. We have shown that bone morphogenetic protein 4 (BMP4) signaling leads to the glomerular changes characteristic of this disorder. To analyze the molecular mechanism of podocyte injury, the effect of BMP4 was investigated using streptozotocin (STZ)-induced, Bmp4 heterozygous knockout (Bmp4+/−) and podocyte-specific Bmp4 knockout mice. Mice with STZ-induced diabetes exhibited glomerular matrix hyperplasia and decreased numbers of podocyte nucleus-specific WT1-positive cells. The number of podocytes and proteinuria were improved in both diabetic Bmp4 knockout mouse models compared to the effects observed in the control mice. The effect of BMP4 overexpression on Bmp4-induced or podocyte-specific transgenic mice was examined. Tamoxifen-induced Bmp4-overexpressing mice exhibited mesangial matrix expansion and decreased numbers of WT1-positive cells. Podocyte-specific Bmp4-overexpressing mice displayed increased kidney BMP4 expression and mesangial matrix expansion but decreased nephrin expression and numbers of WT1-positive cells. Both lines of Bmp4-overexpressing mice exhibited increased albuminuria. In cultured podocytes, BMP4 increased phospho-p38 levels. BMP4 decreased nephrin expression but increased cleaved caspase-3 levels. p38 suppression inhibited caspase-3 activation. Apoptosis was confirmed in STZ-diabetic glomeruli and Bmp4-overexpressing mice. Bmp4 +/− mice with diabetes displayed reduced apoptosis. Based on these data, the BMP4 signaling pathway plays important roles in the development of both podocyte injury and mesangial matrix expansion in diabetic nephropathy. Nature Publishing Group UK 2018-08-29 /pmc/articles/PMC6115362/ /pubmed/30158674 http://dx.doi.org/10.1038/s41598-018-31464-9 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Fujita, Yui
Tominaga, Tatsuya
Abe, Hideharu
Kangawa, Yumi
Fukushima, Naoshi
Ueda, Otoya
Jishage, Kou-ichi
Kishi, Seiji
Murakami, Taichi
Saga, Yumiko
Kanwar, Yashpal S.
Nagai, Kojiro
Doi, Toshio
An adjustment in BMP4 function represents a treatment for diabetic nephropathy and podocyte injury
title An adjustment in BMP4 function represents a treatment for diabetic nephropathy and podocyte injury
title_full An adjustment in BMP4 function represents a treatment for diabetic nephropathy and podocyte injury
title_fullStr An adjustment in BMP4 function represents a treatment for diabetic nephropathy and podocyte injury
title_full_unstemmed An adjustment in BMP4 function represents a treatment for diabetic nephropathy and podocyte injury
title_short An adjustment in BMP4 function represents a treatment for diabetic nephropathy and podocyte injury
title_sort adjustment in bmp4 function represents a treatment for diabetic nephropathy and podocyte injury
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115362/
https://www.ncbi.nlm.nih.gov/pubmed/30158674
http://dx.doi.org/10.1038/s41598-018-31464-9
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