Novel serpinopathy in rat kidney and pancreas induced by overexpression of megsin

Reiko Inagi, Masaomi Nangaku, Nobuteru Usuda, Akira Shimizu, Hiroshi Onogi, Yuko Izuhara, Kiyokazu Nakazato, Yasuhiko Ueda, Hisashi Oishi, Satoru Takahashi, Masayuki Yamamoto, Daisuke Suzuki, Kiyoshi Kurokawa, Charles Van Ypersele De Strihou, Toshio Miyata

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)


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 β 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.

Original languageEnglish
Pages (from-to)1339-1349
Number of pages11
JournalJournal of the American Society of Nephrology : JASN
Issue number5
Publication statusPublished - 2005


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