A biologic- and chemical-induced rat model of glomerular and tubular injury

Nonsurgical rodent chronic kidney disease (CKD) models for both glomerular and tubular injuries are currently limited. This study aimed to develop a rat model of CKD by combining anti-Fx1A with N(ω)-nitrophenyl-L-arginine methyl ester (L-NAME) administration. The rats were assigned to groups receiving L-NAME, anti-Fx1A, anti-Fx1A + L-NAME, or vehicle. Renal function, stiffness, injury biomarkers, histopathology and genome-wide transcriptomic changes were evaluated. Protein and renal injury biomarker levels in the urine were elevated in the anti-Fx1A alone and combination groups. Shear wave elastography revealed increased stiffness of the kidneys in all treatment groups. Histopathological evaluation revealed glomerular injury, characterized by enlarged glomeruli with increased hyaline materials in both anti-Fx1A groups and tubular degeneration/regeneration in the renal cortex of all treated groups, with the highest incidence and severity in the combination group. These tubular changes were sometimes accompanied by interstitial mononuclear cell infiltrates and interstitial fibrosis. Proteinuria and mild changes in blood, urine renal injury biomarkers and imaging endpoints were noted in association with these histopathologic changes. The concurrence and higher incidence and/or severity of glomerular and tubular injuries in the combination group indicate that this would be a useful and relevant CKD model suitable for mechanistic, pharmacologic and toxicological investigations.目前兼具肾小球与肾小管损伤的非手术性啮齿类慢性肾脏病（CKD）模型仍较为匮乏。本研究旨在通过联合给予抗Fx1A与N(ω)-硝基-L-精氨酸甲酯（L-NAME），构建慢性肾脏病大鼠模型。将大鼠随机分为四组：分别给予L-NAME、抗Fx1A、抗Fx1A联合L-NAME，或赋形剂处理。对各组大鼠的肾功能、肾脏硬度、损伤生物标志物、组织病理学以及全基因组转录组变化进行了检测评估。单独给予抗Fx1A组与联合给药组大鼠的尿液中，蛋白质与肾脏损伤生物标志物水平均显著升高。剪切波弹性成像（Shear wave elastography）结果显示，所有给药组大鼠的肾脏硬度均有所升高。组织病理学评估结果显示，两个抗Fx1A组均出现肾小球损伤，特征为肾小球体积增大且透明样物质增多；所有给药组大鼠的肾皮质均出现肾小管变性/再生，其中联合给药组的损伤发生率与严重程度最高。此类肾小管损伤有时还伴随间质单核细胞浸润与间质纤维化。上述组织病理学变化还伴随蛋白尿，以及血液、尿液中肾脏损伤生物标志物与成像检测终点的轻度异常。联合给药组同时出现且发生率和/或严重程度更高的肾小球与肾小管损伤，表明该模型是一款适用于机制研究、药理学与毒理学实验的实用且贴合临床的慢性肾脏病模型。