title: Novel serpinopathy in rat kidney and pancreas induced by overexpression of megsin.
abstract: The intracellular polymerization of abnormal serine protease inhibitors (serpins) results in liver or neuronal cell abnormalities recently identified as "serpinopathies." It was demonstrated in transgenic rats that overexpression of megsin, a recently discovered serpin located in the kidney, produces renal and pancreatic lesions characteristic of serpinopathies. Megsin expression is elevated in a variety of organs, including kidney and pancreas. Periodic acid-Schiff-positive, diastase-resistant intracellular inclusions develop only in the kidney and the pancreas. 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 of glomerular epithelial, distal, and collecting duct cells, 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 beta cells are reduced as a result of apoptosis. They are associated with diabetes with low insulin levels. The animals have an impaired growth and die within 10 wk. Rats that overexpress a mutant megsin, characterized by a deficient conformational transition activity, do not develop the serpinopathy, suggesting that some conformational flexibility of the serpin is required for the development of serpinopathy. This model of serpinopathy is the first to involve the kidney and the pancreas.
authors.affiliation: Molecular and Cellular Nephrology, Institute of Medical Sciences, Tokai University, Kanagawa, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Inagi
authors.forename: Masaomi
authors.initials: M
authors.lastname: Nangaku
authors.forename: Nobuteru
authors.initials: N
authors.lastname: Usuda
authors.forename: Akira
authors.initials: A
authors.lastname: Shimizu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Onogi
authors.forename: Yuko
authors.initials: Y
authors.lastname: Izuhara
authors.forename: Kiyokazu
authors.initials: K
authors.lastname: Nakazato
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Ueda
authors.forename: Hisashi
authors.initials: H
authors.lastname: Oishi
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Daisuke
authors.initials: D
authors.lastname: Suzuki
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kurokawa
authors.forename: Charles
authors.initials: C
authors.lastname: van Ypersele de Strihou
authors.forename: Toshio
authors.initials: T
authors.lastname: Miyata
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D005260:Female; D015870:Gene Expression; D006801:Humans; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D010179:Pancreas / Q000473:pathology / Q000503:physiopathology; D010182:Pancreatic Diseases / Q000401:mortality / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D015843:Serpins / Q000235:genetics*
chemical_list: C114170:SERPINB7 protein, human; D015843:Serpins