Gubra Aps, Horsholm, Denmark.
Am J Physiol Renal Physiol. 2021 Aug 1;321(2):F149-F161. doi: 10.1152/ajprenal.00154.2021. Epub 2021 Jun 28.
Hypertension is a critical comorbidity for progression of diabetic kidney disease (DKD). To facilitate the development of novel therapeutic interventions with the potential to control disease progression, there is a need to establish translational animal models that predict treatment effects in human DKD. The present study aimed to characterize renal disease and outcomes of standard of medical care in a model of advanced DKD facilitated by adeno-associated virus (AAV)-mediated renin overexpression in uninephrectomized (UNx) mice. Five weeks after single AAV administration and 4 wk after UNx, female UNx-ReninAAV mice received (PO, QD) vehicle, lisinopril (40 mg/kg), empagliflozin (20 mg/kg), or combination treatment for 12 wk ( = 17 mice/group). Untreated /+ mice ( = 8) and vehicle-dosed UNx-LacZAAV mice ( = 17) served as controls. End points included plasma, urine, and histomorphometric markers of kidney disease. Total glomerular numbers and individual glomerular volume were evaluated by whole kidney three-dimensional imaging analysis. UNx-ReninAAV mice developed hallmarks of progressive DKD characterized by severe albuminuria, advanced glomerulosclerosis, and glomerular hypertrophy. Lisinopril significantly improved albuminuria, glomerulosclerosis, tubulointerstitial injury, and inflammation. Although empagliflozin alone had no therapeutic effect on renal endpoints, lisinopril and empagliflozin exerted synergistic effects on renal histological outcomes. In conclusion, the UNx-ReninAAV mouse demonstrates good clinical translatability with respect to physiological and histological hallmarks of progressive DKD. The efficacy of standard of care to control hypertension and hyperglycemia provides a proof of concept for testing novel drug therapies in the model. Translational animal models of diabetic kidney disease (DKD) are important tools in preclinical research and drug discovery. Here, we show that the standard of care to control hypertension (lisinopril) and hyperglycemia (empagliflozin) improves physiological and histopathological hallmarks of kidney disease in a mouse model of hypertension-accelerated progressive DKD. The findings substantiate hypertension and type 2 diabetes as essential factors in driving DKD progression and provide a proof of concept for probing novel drugs for potential nephroprotective efficacy in this model.
高血压是糖尿病肾病（DKD）进展的关键合并症。为了促进具有控制疾病进展潜力的新型治疗干预措施的发展，需要建立能够预测人类 DKD 治疗效果的转化动物模型。本研究旨在通过腺相关病毒（AAV）介导的肾素过表达，在单侧肾切除（UNx）小鼠中建立晚期 DKD 模型，以确定该模型中肾脏疾病的特征和标准治疗的结果。在单次 AAV 给药后 5 周和 UNx 后 4 周，雌性 UNx-ReninAAV 小鼠接受（PO，QD）载体、赖诺普利（40mg/kg）、恩格列净（20mg/kg）或联合治疗 12 周（每组 17 只小鼠）。未治疗的+/+小鼠（n=8）和接受载体处理的 UNx-LacZAAV 小鼠（n=17）作为对照。终点包括血浆、尿液和肾脏疾病的组织形态计量学标志物。通过全肾三维成像分析评估肾小球总数和单个肾小球体积。UNx-ReninAAV 小鼠出现了进行性 DKD 的特征性标志，包括严重的白蛋白尿、晚期肾小球硬化和肾小球肥大。赖诺普利显著改善了白蛋白尿、肾小球硬化、肾小管间质损伤和炎症。尽管恩格列净单独治疗对肾脏终点没有治疗作用，但赖诺普利和恩格列净对肾脏组织学结果具有协同作用。总之，UNx-ReninAAV 小鼠在进行性 DKD 的生理和组织学特征方面具有良好的临床转化性。控制高血压和高血糖的标准治疗为该模型中新型药物治疗的测试提供了概念验证。糖尿病肾病（DKD）的转化动物模型是临床前研究和药物发现的重要工具。在这里，我们表明，控制高血压（赖诺普利）和高血糖（恩格列净）的标准治疗改善了高血压加速进行性 DKD 小鼠模型中肾脏疾病的生理和组织病理学特征。这些发现证实了高血压和 2 型糖尿病是推动 DKD 进展的关键因素，并为在该模型中探索潜在的肾脏保护作用的新型药物提供了概念验证。
