2004 Fiscal Year Final Research Report Summary
Molecular biological function of mesangium predominantly expressed gene, megsin
| Project/Area Number |
15590861
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Kidney internal medicine
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| Research Institution | Tokai University |
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Principal Investigator |
INAGI Reiko Tobkai University, Medical Research Institute, Associate Proissor, 総合医学研究所, 助教授 (50232509)
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| Project Period (FY) |
2003 – 2004
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| Keywords | serine protease inhibitor / renal failure / serpinopathy / proteinuria / podocytes / endoplasmic reticulum stress / glomerular injuru / transgenic animal |
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| Research Abstract |
The intracellular polymerization of abnormal serine protease inhibitors (serpins) results in liver or neuronal cell abnormalities recently identified as "serpinopathies". We demonstrate in transgenic rats overexpressing megsin, a recently discovered serpin located in the kidney, produce renal and pancreatic lesions characteristic of serpinopathies. Megsin expression is elevated in a variety of organs including kidney and pancreas. Periodic acid Schiff-positive intracellular inclusions develop only in the two latter organs. They correspond to electron dense deposits, shown to contain megsin by immunohistochemistry and immunoelectron microscopy. In the kidney, inclusions are located mainly in the endoplasmic reticulum (ER) of glomerular epithelial, distal tubules and collecting ducts and are associated with massive proteinuria and an impaired renal function. In the pancreas, similar inclusions are found in the exocrine and Langerhans islet cells, where islet b-cells are reduced due to apoptosis. They are associated with diabetes with low insulin levels. An imbalance between protein load and folding capacity is referred to as ER stress. As a defense mechanism, cells express ER stress inducible chaperons such as oxygen regulated protein 150 (ORP150) and glucose regulated proteins (GRPs). The expression level of ORP150 and GRPs were markedly up-regulated in podocytes of megsin transgenic rats, subsequently developed podocyte injury. Rats overexpressing a mutant megsin, characterized by a deficient conformational transition activity, do not develop the serpinopathy associated with renal dysfunction, proteinuria, hyperglycemia and ER stress, suggesting that some conformational flexibility of the serpin is required for the development of serpinopathy. The present model of serpinopathy is the first to involve the kidney and pancreas, and demonstrates a crucial role for ER stress in podocyte injury.
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Research Products
(42 results)
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[Journal Article] Affinity adsorption of glucose degradation products improves the biocompatibility of conventional peritoneal dialysis fluid2003
Author(s)
Ishikawa N, Miyata T, Ueda Y, magi R, Izuhara Y, Yuzawa H, Onogi H, Nishina M, Nangaku M, Van Ypersele De Strihou C, Kurokawa K.
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Journal Title
Kidney Int 63
Pages: 331-339
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Human herpesvirus 6B infection of the large intestine of patients with diarrhea2003
Author(s)
Amo K, Tanaka-Taya K, magi R, Miyagawa H, Miyoshi H, Okusu I, Sashihara J, Hara J, Nakayama M, Yamanishi K, Okada S.
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Journal Title
Clin Infect Dis 36
Pages: 120-3
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Anti-hypertensive agents inhibit in vivo the formation of advanced glycation end products and improve renal damage in a type 2 diabetic nephropathy rat model2003
Author(s)
Nangaku M, Miyata T, Sada T, Mizuno M, Inagi R, Ueda Y, Ishikawa N, Yuzawa H, Koike H, Van Ypersele De Strihou C, Kurokawa K.
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Journal Title
J Am Soc Nephrol 14
Pages: 1212-22
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] A novel serpinopathy -in rat kidney and pancreas induced by overexpression of megsin
Author(s)
Inagi R, Miyata T, Nangaku M, Usuda N, Shimizu A, Izuhara Y.Onogi H, Ueda Y, Nakazato K, Oishi H, Takahashi, S, Yamamoto M, van Ypersele de Strihou C, Kukokawa K.
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Journal Title
J Am Soc Nephrol (in press)
Description
「研究成果報告書概要(欧文)」より
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