The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huaian, Jiangsu 223001, China.
Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210003, China.
Biochim Biophys Acta Mol Basis Dis. 2023 Jun;1869(5):166705. doi: 10.1016/j.bbadis.2023.166705. Epub 2023 Apr 5.
Podocytes have been indicated to be a critical factor for the development of diabetic kidney disease. Podocyte loss leads to irreversible glomerular injury and proteinuria in animal models. As terminal differentiated cells, autophagy is crucial for maintaining podocyte homeostasis. Previous studies have shown that Uncoupling proteins 2 (UCP2) regulate fatty acid metabolism, mitochondrial calcium uptake and reactive oxygen species (ROS) production. This study aimed to investigate whether UCP2 promote autophagy in podocyte and further explore the regulation mechanism of UCP2.
For podocyte-specific UCP2-KO mice, we cross bred UCP2f mouse strain with the podocin-Cre mice. Diabetic mice were obtained by daily intraperitoneally injections of 40 mg/kg streptozotocin for 3 days. After 6 weeks, mice were scarified, and kidney tissues were analyzed by histological stain, Western blot, Immunofluorescence, and immunohistochemistry. Also, urine samples were collected for protein quantification. For in vitro study, podocytes were primary cultured from UCP2f mouse or transfected with adeno-associated virus (AAV)-UCP2.
Diabetic kidney showed elevated expression of UCP2 and specific ablation of UCP2 in podocyte aggravates diabetes-induced albuminuria and glomerulopathy. UCP2 protects hyperglycemia-induced podocyte injury by promoting autophagy in vivo and in vitro. Rapamycin treatment significantly ameliorates streptozotocin (STZ)-induced podocyte injury in UCP2 mice.
UCP2 expression in podocyte increased under diabetic condition and appeared to be an initial compensatory response. UCP2 deficiency in podocyte impaired autophagy and exacerbates podocyte injury and proteinuria in diabetic nephropathy.
足细胞被认为是糖尿病肾病发展的关键因素。在动物模型中，足细胞丢失会导致不可逆转的肾小球损伤和蛋白尿。作为终末分化细胞，自噬对于维持足细胞内稳态至关重要。先前的研究表明，解偶联蛋白 2（UCP2）调节脂肪酸代谢、线粒体钙摄取和活性氧（ROS）的产生。本研究旨在探讨 UCP2 是否促进足细胞自噬，并进一步探索 UCP2 的调节机制。
对于足细胞特异性 UCP2-KO 小鼠，我们将 UCP2f 小鼠与 podocin-Cre 小鼠杂交。通过每天腹腔内注射 40mg/kg 链脲佐菌素（STZ）3 天来制备糖尿病小鼠。6 周后，处死小鼠，通过组织学染色、Western blot、免疫荧光和免疫组化分析肾脏组织。此外，收集尿液样本进行蛋白定量。对于体外研究，我们从 UCP2f 小鼠或转染腺相关病毒（AAV）-UCP2 的原代培养的足细胞中进行研究。
糖尿病肾脏中 UCP2 的表达升高，特异性敲除足细胞中的 UCP2 会加重糖尿病引起的白蛋白尿和肾小球病变。UCP2 通过在体内和体外促进自噬来保护高血糖诱导的足细胞损伤。雷帕霉素处理可显著改善 UCP2 小鼠的 STZ 诱导的足细胞损伤。
在糖尿病条件下，足细胞中的 UCP2 表达增加，这似乎是一种初始的代偿反应。足细胞中 UCP2 的缺乏会损害自噬，并加重糖尿病肾病中的足细胞损伤和蛋白尿。
