Delagado Rachel D, de Caestecker Mark P
Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center.
Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center;
J Vis Exp. 2025 Jul 18(221). doi: 10.3791/68492.
Clinical management of patients with urinary tract obstruction (UTO) requires early intervention to reverse the cause of the obstruction, but despite this, patients with prolonged UTO are at increased risk of chronic kidney disease (CKD) and recurrent acute kidney injury (AKI). However, other than an early reversal of obstruction and generic therapy to delay CKD progression, no therapies have significantly improved long-term renal outcomes after the reversal of UTO. To address this, a number of laboratories have developed models of reversible UUO (R-UUO), but these are technically challenging and have not been widely adopted. In addition, while mouse models of R-UUO are attractive as they can be used to harness the power of mouse genetics to study disease pathophysiology, these have been particularly challenging as methods used often lead to irreversible UUO if the obstruction lasts >3 days. In addition, because of the nature of these models, few studies have evaluated the long-term functional outcomes of reversing ureteric obstruction. To address this, we recently developed a mouse model of R-UUO with delayed contralateral nephrectomy that allows for the analysis of the long-term effects of reversing prolonged UTO on long-term renal structural and functional outcomes. These studies show that despite near complete histological recovery 3 months after reversal, there was a permanent reduction in renal function and a marked and persistent defect in urinary concentrating capacity, indicative of a defect in renal medullary function. The model requires three major survival surgeries but results in a robust and reproducible long-term reduction in renal function that can be reproduced in different mouse strains by adjusting the period of obstruction. In this article, we provide detailed instructions for performing these surgeries, optimizing conditions for use in different mouse strains, evaluating renal functional outcomes, and harvesting renal tissues.
尿路梗阻（UTO）患者的临床管理需要早期干预以消除梗阻原因，但即便如此，UTO持续时间较长的患者患慢性肾脏病（CKD）和复发性急性肾损伤（AKI）的风险仍会增加。然而，除了早期解除梗阻以及采用延缓CKD进展的通用疗法外，UTO解除后，尚无其他疗法能显著改善长期肾脏预后。为解决这一问题，多个实验室已开发出可逆性单侧输尿管梗阻（R-UUO）模型，但这些模型在技术上具有挑战性，尚未得到广泛应用。此外，虽然R-UUO小鼠模型很有吸引力，因为可利用小鼠遗传学的力量来研究疾病病理生理学，但这些模型尤其具有挑战性，因为如果梗阻持续超过3天，常用方法往往会导致不可逆的UUO。此外由于这些模型的特性，很少有研究评估解除输尿管梗阻的长期功能预后。为解决这一问题，我们最近开发了一种带有延迟对侧肾切除术的R-UUO小鼠模型，该模型可用于分析解除长期UTO对长期肾脏结构和功能预后的长期影响。这些研究表明，尽管解除梗阻3个月后组织学几乎完全恢复，但肾功能出现了永久性下降，尿浓缩能力存在明显且持续的缺陷，这表明肾髓质功能存在缺陷。该模型需要进行三次大型存活手术，但会导致肾功能出现显著且可重复的长期下降，通过调整梗阻时间，可在不同小鼠品系中重现这一现象。在本文中，我们提供了实施这些手术、优化不同小鼠品系使用条件、评估肾功能预后以及获取肾组织的详细说明。
