| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2003: ¥2,200,000 (Direct Cost: ¥2,200,000)
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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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