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Novel Treatment for Lithium-Induced Nephrogenic Diabetes Insipidus Rat Model Using the Sendai-Virus Vector Carrying Aquaporin 2 Gene

Department of Endocrinology and Diabetes (H.S., T.K., Y.Ok., C.S., Nobua.O., H.A., Y.On., Field of Internal Medicine, Department of Metabolic Medicine (H.N.), and Departments of Urology (T.Y.) and Functional Anatomy and Neuroscience (Nobuy.O.), Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Bioscience and Biotechnology Center (M.A., A.S., N.U.), Nagoya University, Nagoya 464-8601, Japan; Department of Biomolecular Engineering 1 (N.U.), Graduate School of Engineering, Tohoku University, Sendai 980-8579, Japan; and DNAVEC Research Inc. (M.I., M.H.), Ibaraki 305-0856, Japan

Address all correspondence and requests for reprints to: Dr. Hiroshi Nagasaki, Department of Metabolic Medicine, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan. E-mail: nagasaki{at}med.nagoya-u.ac.jp.

Congenital nephrogenic diabetes insipidus (NDI) is a chronic disorder involving polyuria and polydipsia that results from unresponsiveness of the renal collecting ducts to the antidiuretic hormone vasopressin. Either of the genetic defects in vasopressin V2 receptor or the water channel aquaporin 2 (AQP2) cause the disease, which interfere the water reabsorption at the epithelium of the collecting duct. An unconscious state including a perioperative situation can be life threatening because of the difficulty to regulate their water balance. The Sendai virus (SeV) vector system deleting fusion protein (F) gene (SeV/F) is considered most suitable because of the short replication cycle and nontransmissible character. An animal model for NDI with reduced AQP2 by lithium chloride was used to develop the therapy. When the SeV/F vector carrying a human AQP2 gene (AQP2-SeV/F) was administered retrogradely via ureter to renal pelvis, AQP2 was expressed in the renal collecting duct to reduce urine output and water intake by up to 40%. In combination with the retorograde administration to pelvis, this system could be the cornerstone for the applicable therapies on not only NDI patients but also other diseases associate with the medullary collecting duct.