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FSGS as an Adaptive Response to Growth-Induced Podocyte Stress
http://hdl.handle.net/10458/6183
http://hdl.handle.net/10458/618389ae6cad-2703-4907-8e2a-5efd361083a4
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論文要旨 (59.6 kB)
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学位論文審査結果の要旨 (24.3 kB)
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博士学位論文 (4.2 MB)
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| Item type | 学位論文 / Thesis or Dissertation(1) | |||||
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| 公開日 | 2020-06-21 | |||||
| タイトル | ||||||
| タイトル | FSGS as an Adaptive Response to Growth-Induced Podocyte Stress | |||||
| 言語 | en | |||||
| 言語 | ||||||
| 言語 | eng | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_db06 | |||||
| 資源タイプ | doctoral thesis | |||||
| アクセス権 | ||||||
| アクセス権 | open access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_abf2 | |||||
| 著者 |
西園, 隆三
× 西園, 隆三 |
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| 内容記述タイプ | Abstract | |||||
| 内容記述 | Glomerular sclerotic lesions develop when the glomerular filtration surface area exceeds the availability of podocyte foot process coverage, but the mechanisms involved are incompletely characterized. We evaluated potential mechanisms using a transgenic (podocin promoter-AA-4E-BP1) rat in which podocyte capacity for hypertrophy in response to growth factor/nutrient signaling is impaired. FSGS lesions resembling human FSGS developed spontaneously by 7 months of age, and could be induced earlier by accelerating kidney hypertrophy by nephrectomy. Early segmental glomerular lesions occurred in the absence of a detectable reduction in average podocyte number per glomerulus and resulted from the loss of podocytes in individual glomerular capillary loops. Parietal epithelial cell division, accumulation on Bowman's capsule, and tuft invasion occurred at these sites. Three different interventions that prevented kidney growth and glomerular enlargement (calorie intake reduction, inhibition of mammalian target of rapamycin complex, and inhibition of angiotensin-converting enzyme) protected against FSGS lesion development, even when initiated late in the process. Ki67 nuclear staining and unbiased transcriptomic analysis identified increased glomerular (but not podocyte) cell cycling as necessary for FSGS lesion development. The rat FSGS-associated transcriptomic signature correlated with human glomerular transcriptomes associated with disease progression, compatible with similar processes occurring in man. We conclude that FSGS lesion development resulted from glomerular growth that exceeded the capacity of podocytes to adapt and adequately cover some parts of the filtration surface. Modest modulation of the growth side of this equation significantly ameliorated FSGS progression, suggesting that glomerular growth is an underappreciated therapeutic target for preservation of renal function. | |||||
| 言語 | en | |||||
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| 本論文に関連する研究論文 Nishizono R, Kikuchi M, Wang SQ, Chowdhury M, Nair V, Hartman J, Fukuda A, Wickman L, Hodgin JB, Bitzer M, Naik A, Wiggins J, Kretzler M, Wiggins RC. FSGS as an Adaptive Response to Growth-Induced Podocyte Stress. J Am Soc Nephrol. 2017 Oct;28(10):2931-2945. doi: 10.1681/ASN.2017020174. Epub 2017 Jul 18. PMID: 28720684; PMCID: PMC5619973. |
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| 学位名 | ||||||
| 言語 | ja | |||||
| 学位名 | 博士(医学) | |||||
| 学位授与機関 | ||||||
| 学位授与機関識別子Scheme | kakenhi | |||||
| 学位授与機関識別子 | 17601 | |||||
| 言語 | ja | |||||
| 学位授与機関名 | 宮崎大学 | |||||
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| 内容記述タイプ | Other | |||||
| 内容記述 | 2016年度 | |||||
| 言語 | ja | |||||
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| 学位授与年月日 | 2017-03-24 | |||||
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| 学位授与番号 | 医博甲第441号 | |||||
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| 出版タイプ | VoR | |||||
| 出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 | |||||
| リンク |
FSGS as an Adaptive Response to Growth-Induced Podocyte Stress
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