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Abstract
Congenital nephrogenic diabetes insipidus (NDI) is a hereditary disease characterized by a reduced response to arginine vasopressin in the renal collecting duct. NDI is primarily caused by mutations in the arginine vasopressin receptor 2 (AVPR2). Several animal models have been developed for congenital NDI; however, the appropriate models are limited. Thus, we constructed a novel Avpr2-deficient rat model using gene-editing technology to study the pathophysiological mechanisms of NDI. Avpr2-deficient rats were generated via a novel genome editing approach termed the rat Genome-editing via Oviductal Nucleic Acid Delivery (rGONAD) method. The phenotypes were analyzed using biological, molecular, and histological examinations. The effects of hydrochlorothiazide (40mg/kg/d) on 24-h water intake, urine volume, and urine osmolality were evaluated in a metabolic cage. Avpr2-deficient rats were born and weaned under normal rearing conditions and exhibited symptoms similar to those of human congenital NDI, such as polydipsia, polyuria, and growth retardation. Although they exhibited hydronephrosis-like kidneys, no glomerular or tubular damage was observed. Aquaporin-2 was retained in the cytoplasm of collecting duct cells, and its phosphorylation was suppressed. Administration of hydrochlorothiazide decreased urine volume and improved urine osmolality in Avpr2-deficient rats. Avpr2-deficient rats are a reliable model of congenital NDI for elucidating the underlying mechanisms and identifying therapeutic targets.
Published Version
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