Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
J Am Soc Nephrol. 2011 Jul;22(7):1275-85. doi: 10.1681/ASN.2010090963. Epub 2011 Jun 30.
Loss of podocytes promotes glomerulosclerosis, but whether this results from a continued primary insult or a secondary mechanism triggered by the initial loss of podocytes is unknown. We generated chimeric mice in which only a subpopulation of podocytes expressed hCD25, which is the receptor for the immunotoxin LMB2. In addition, genetic labeling of hCD25-negative cells with human placental alkaline phosphatase allowed the study of these two distinct podocyte populations. Administration of LMB2 did not cause podocyte injury in hCD25-negative control mice. In contrast, LMB2 severely damaged or sloughed off the subpopulation of hCD25-positive podocytes within the chimeric glomeruli. Moreover, hCD25-negative podocytes, which were immune to the initial toxin injury, developed injury as early as 4 d after LMB2 injection, evidenced by foot process effacement, upregulation of desmin, and downregulation of nephrin, podocin, and podocalyxin. Furthermore, the magnitude of secondary injury correlated with the magnitude of primary injury, supporting the concept of an amplified cascade of podocyte injury. In conclusion, podocyte damage can propagate injury by triggering secondary damage of "remnant" intact podocytes, even when the primary insult is short-lived. This transmission of podocyte injury may form a vicious cycle leading to accelerated podocyte deterioration and glomerulosclerosis.
足细胞丢失会促进肾小球硬化，但这种情况是源于持续的原发性损伤，还是源于足细胞初始丢失所触发的继发性机制尚不清楚。我们构建了嵌合小鼠，其中只有一部分足细胞表达 hCD25，而 hCD25 是免疫毒素 LMB2 的受体。此外，用人胎盘碱性磷酸酶对 hCD25 阴性细胞进行遗传标记，可研究这两种不同的足细胞群体。在 hCD25 阴性对照小鼠中，LMB2 并未引起足细胞损伤。相比之下，LMB2 严重损害或从嵌合肾小球中 hCD25 阳性足细胞亚群中脱落。此外，最初对毒素损伤具有免疫力的 hCD25 阴性足细胞，在 LMB2 注射后 4 天即可出现损伤，表现为足突消失、结蛋白上调以及nephrin、podocin 和 podocalyxin 下调。此外，继发性损伤的程度与原发性损伤的程度相关，支持足细胞损伤放大级联的概念。总之，足细胞损伤可通过触发“残余”完整足细胞的继发性损伤来传播损伤，即使原发性损伤是短暂的。这种足细胞损伤的传递可能形成一个恶性循环，导致足细胞恶化和肾小球硬化加速。
