Bohnert Bernhard N, Artunc Ferruh
Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University Hospital Tübingen; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, University Tübingen; German Center for Diabetes Research (DZD), University Tübingen.
Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University Hospital Tübingen; Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, University Tübingen; German Center for Diabetes Research (DZD), University Tübingen;
J Vis Exp. 2018 May 6(135):57642. doi: 10.3791/57642.
Nephrotic syndrome is the most extreme manifestation of proteinuric kidney disease and characterized by heavy proteinuria, hypoalbuminemia, and edema due to sodium retention and hyperlipidemia. To study the pathophysiology of this syndrome, rodent models have been developed based on the injection of toxic substances such as doxorubicin causing podocyte damage. In mice, only few strains are susceptible to this model. In wildtype 129S1/SvImJ mice, the administration of doxorubicin by rapid intravenous injection to the retrobulbar sinus induces experimental nephrotic syndrome that features all the symptoms of human disease including sodium retention and edema. After the onset of proteinuria, mice exhibit increased urinary serine protease activity that leads to the activation of the epithelial sodium channel (ENaC) and sodium retention. Pharmacological inhibition of urinary serine proteases by the treatment with sustained release aprotinin abrogates ENaC activation and prevents sodium retention. This model is ideal to study the pathophysiology of proteasuria, i.e., the excretion of active serine proteases that cause ENaC activation by the proteolysis of its γ-subunit. This can be regarded as the primary mechanism of ENaC activation and sodium retention in proteinuric kidney disease.
肾病综合征是蛋白尿性肾脏疾病最严重的表现形式，其特征为大量蛋白尿、低白蛋白血症，以及因钠潴留和高脂血症导致的水肿。为研究该综合征的病理生理学，已基于注射多柔比星等导致足细胞损伤的有毒物质建立了啮齿动物模型。在小鼠中，只有少数品系对该模型敏感。在野生型129S1/SvImJ小鼠中，通过快速静脉注射将多柔比星注入球后窦可诱发实验性肾病综合征，该综合征具有人类疾病的所有症状，包括钠潴留和水肿。蛋白尿出现后，小鼠尿丝氨酸蛋白酶活性增加，导致上皮钠通道（ENaC）激活和钠潴留。通过持续释放抑肽酶治疗对尿丝氨酸蛋白酶进行药理抑制可消除ENaC激活并预防钠潴留。该模型是研究蛋白酶尿病理生理学的理想模型，即通过其γ亚基的蛋白水解导致ENaC激活的活性丝氨酸蛋白酶的排泄。这可被视为蛋白尿性肾脏疾病中ENaC激活和钠潴留的主要机制。
