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ID 112896
Title Alternative
BMP4の機能調節は糖尿病性腎症及びポドサイト障害の治療につながる
Author
Fujita, Yui Tokushima University
Kangawa, Yumi Tokushima University
Fukushima, Naoshi Chugai Pharmaceutical Co., Ltd
Ueda, Otoya Chugai Pharmaceutical Co., Ltd
Jishage, Kou-ichi Chugai Pharmaceutical Co., Ltd|Chugai Research Institute for Medical Science Inc.
Saga, Yumiko National Institute of Genetics
Kanwar, Yashpal S. Northwestern University
Keywords
Podocyte
cytokine
diabetic nephropathy
BMP4
CKD
Content Type
Thesis or Dissertation
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.
Journal Title
Scientific Reports
ISSN
20452322
Publisher
Springer Nature
Volume
8
Start Page
13011
Published Date
2018-08-29
Remark
内容要旨・審査要旨・論文本文の公開
本論文は, 著者Yui Fujitaの学位論文として提出され, 学位審査・授与の対象となっている。
Rights
© The Author(s) 2018 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/.
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第3240号
Diploma Number
甲医第1389号
Granted Date
2018-10-25
Degree Name
Doctor of Medical Science
Grantor
Tokushima University
departments
Medical Sciences
University Hospital