1 Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido 060-0818, Japan.
2 Section of Biological Science, Chitose Laboratory, Japan Food Research Laboratories, Chitose, Hokkaido 066-0052, Japan.
Exp Biol Med (Maywood). 2018 Mar;243(5):418-427. doi: 10.1177/1535370218758250. Epub 2018 Feb 7.
Cotton rat ( Sigmodon hispidus) is a useful experimental rodent for the study of human infectious diseases. We previously clarified that cotton rats, particularly females, developed chronic kidney disease characterized by cystic lesions, inflammation, and fibrosis. The present study investigated female-associated factors for chronic kidney disease development in cotton rats. Notably, female cotton rats developed separation of the pelvic symphysis and hypertrophy in the vaginal parts of the cervix with age, which strongly associated with pyometra. The development of pyometra closely associated with the deterioration of renal dysfunction or immunological abnormalities was indicated by blood urea nitrogen and serum creatinine or spleen weight and serum albumin/globulin ratio, respectively. These parameters for renal dysfunction and immunological abnormalities were statistically correlated. These phenotypes found in the female reproductive organs were completely inhibited by ovariectomy. Further, the female cotton rats with pyometra tended to show more severe chronic kidney disease phenotypes and immunological abnormalities than those without pyometra; these changes were inhibited in ovariectomized cotton rats. With regard to renal histopathology, cystic lesions, inflammation, and fibrosis were ameliorated by ovariectomy. Notably, the immunostaining intensity of estrogen receptor α and estrogen receptor β were weak in the healthy kidneys, but both estrogen receptors were strongly induced in the renal tubules showing cystic changes. In conclusion, the close correlations among female reproductive organ-associated abnormalities, immunological abnormalities, and renal dysfunction characterize the chronic kidney disease features of female cotton rats. Thus, the cotton rat is a unique rodent model to elucidate the pathological crosstalk between chronic kidney disease and sex-related factors. Impact statement The increasing number of elderly individuals in the overall population has led to a concomitant age-related increase in chronic kidney disease. Moreover, the global prevalence of patients with chronic kidney disease is gradually increasing, which poses a serious public health problem. The limited number of spontaneous chronic kidney disease animal models, which resemble chronic kidney disease pathogenesis in elderly individuals, is a major limitation in the development of experimental and curative medicines for chronic kidney disease. This pathological study clarified that sex-related factors, including hormones, and abnormalities of the female reproductive system, such as pyometra, are closely associated with chronic kidney disease development by using cotton rats ( Sigmodon hispidus). Further, ovariectomy inhibited the phenotypes of the female reproductive system, immunological abnormalities, and chronic kidney disease. Thus, this laboratory rodent serves as a novel and useful spontaneous chronic kidney disease model to elucidate the candidate disease factors and the pathogenesis of chronic kidney disease both in human and experimental medicine.
棉鼠（Sigmodon hispidus）是研究人类传染病的一种有用的实验动物。我们之前已经阐明，棉鼠，尤其是雌性，会发展为以囊性病变、炎症和纤维化为特征的慢性肾病。本研究调查了棉鼠慢性肾病发展的与雌性相关的因素。值得注意的是，雌性棉鼠随着年龄的增长，会出现骨盆联合分离和宫颈阴道部分的肥大，这与子宫积脓密切相关。子宫积脓的发展与肾功能恶化或免疫异常密切相关，分别表现为血尿素氮和血清肌酐或脾脏重量和血清白蛋白/球蛋白比值的升高。这些肾功能和免疫异常的参数呈统计学相关。这些在雌性生殖器官中发现的表型完全被卵巢切除术抑制。此外，患有子宫积脓的雌性棉鼠往往比没有子宫积脓的棉鼠表现出更严重的慢性肾病表型和免疫异常；这些变化在卵巢切除的棉鼠中受到抑制。关于肾脏组织病理学，囊性病变、炎症和纤维化通过卵巢切除术得到改善。值得注意的是，在健康肾脏中，雌激素受体α和雌激素受体β的免疫染色强度较弱，但在出现囊性变化的肾小管中，这两种雌激素受体均被强烈诱导。总之，与雌性生殖器官相关的异常、免疫异常和肾功能障碍之间的密切关联是雌性棉鼠慢性肾病特征的基础。因此，棉鼠是一种独特的啮齿动物模型，可用于阐明慢性肾病与性别相关因素之间的病理串扰。
