Kamada Ayaka, Hirose Takuo, Sato Shigemitsu, Takahashi Chika, Kaburaki Takahito, Sato Kaori, Ishikawa Risa, Endo Akari, Ito Hiroki, Oba-Yabana Ikuko, Nakamura Hannah, Matsuyama Makoto, Mori Takefumi
Division of Nephrology and Endocrinology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino, Sendai, 983-8536, Japan.
Division of Integrative Renal Replacement Therapy, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan.
Clin Exp Nephrol. 2025 Mar 18. doi: 10.1007/s10157-025-02652-5.
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 (40 mg/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.
先天性肾性尿崩症（NDI）是一种遗传性疾病，其特征是肾集合管对精氨酸加压素的反应降低。NDI主要由精氨酸加压素受体2（AVPR2）突变引起。已经开发了几种先天性NDI的动物模型；然而，合适的模型有限。因此，我们使用基因编辑技术构建了一种新型的Avpr2基因敲除大鼠模型，以研究NDI的病理生理机制。
通过一种称为输卵管核酸递送大鼠基因组编辑（rGONAD）的新型基因组编辑方法生成Avpr2基因敲除大鼠。使用生物学、分子和组织学检查分析表型。在代谢笼中评估氢氯噻嗪（40mg/kg/d）对24小时饮水量、尿量和尿渗透压的影响。
Avpr2基因敲除大鼠在正常饲养条件下出生并断奶，表现出与人类先天性NDI相似的症状，如多饮、多尿和生长发育迟缓。虽然它们表现出类似肾积水的肾脏，但未观察到肾小球或肾小管损伤。水通道蛋白-2保留在集合管细胞的细胞质中，其磷酸化受到抑制。给予氢氯噻嗪可减少Avpr2基因敲除大鼠的尿量并改善尿渗透压。
Avpr2基因敲除大鼠是一种可靠的先天性NDI模型，可用于阐明潜在机制和确定治疗靶点。
