Research Institute of Nephrology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
Kidney Int. 2010 Jun;77(11):974-88. doi: 10.1038/ki.2010.41. Epub 2010 Mar 10.
Membranous nephropathy is a major cause of nephrotic syndrome in adults where podocyte injuries were found to mediate the development of proteinuria. Triptolide, a major active component of Tripterygium wilfordii Hook F, has potent immunosuppressive, anti-inflammatory and antiproteinuric effects. To study its antiproteinuric properties, we established an experimental rat model of passive Heymann nephritis and a C5b-9 injury model of podocytes in vitro. Treatment or pretreatment with triptolide markedly reduced established proteinuria as well as the titer of circulating rat anti-rabbit IgG antibodies in these nephritic rats, accompanied by a reduction in glomerular C5b-9 deposits. Expression of desmin, a marker of podocyte injury, diminished after triptolide treatment, whereas quantitative analysis of mean foot process width showed that effacement of foot processes was substantially reversed. In in vitro studies we found that triptolide deactivated NADPH oxidase, suppressed reactive oxygen species generation and p38 mitogen-activated protein kinase, and restored RhoA signaling activity. Triptolide did not interfere with the formation of C5b-9 on the membrane of podocytes. Thus, triptolide reduces established heavy proteinuria and podocyte injuries in rats with passive Heymann nephritis, and protects podocytes from C5b-9-mediated injury.
膜性肾病是成人肾病综合征的主要病因，其中足细胞损伤被认为介导了蛋白尿的发生。雷公藤红素是雷公藤的主要活性成分之一，具有强大的免疫抑制、抗炎和抗蛋白尿作用。为了研究其抗蛋白尿特性，我们建立了被动性 Heymann 肾炎大鼠模型和体外 C5b-9 损伤的足细胞模型。雷公藤红素治疗或预处理明显减少了这些肾炎大鼠已建立的蛋白尿以及循环大鼠抗兔 IgG 抗体的滴度，同时减少了肾小球 C5b-9 沉积。雷公藤红素治疗后足细胞损伤标志物 desmin 的表达减少，而足突宽度的定量分析表明，足突的融合得到了很大程度的逆转。在体外研究中，我们发现雷公藤红素使 NADPH 氧化酶失活，抑制活性氧的产生和 p38 丝裂原活化蛋白激酶，并恢复 RhoA 信号活性。雷公藤红素不干扰 C5b-9 在足细胞膜上的形成。因此，雷公藤红素可减少被动性 Heymann 肾炎大鼠已建立的大量蛋白尿和足细胞损伤，并保护足细胞免受 C5b-9 介导的损伤。
