Tolvaptan, a selective oral vasopressin V2 receptor antagonist, ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats
Tolvaptan, a selective oral vasopressin V2 receptor antagonist, ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats
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DOI：
10.1007/s10157-009-0196-0
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发表时间：
2009-10-01
影响因子：
2.3
通讯作者：
Shigematsu, Takashi
中科院分区：
文献类型：
--
作者：
Okada, Tadashi;Sakaguchi, Toshifumi;Shigematsu, Takashi
肾小球疾病引起的蛋白尿以足细胞损伤为特征。加压素V2受体拮抗剂可有效减少白蛋白尿，但其对肾小球足细胞的作用尚未研究。本研究的目的是评价选择性口服V2受体拮抗剂托伐普坦（tolvaptan）对嘌呤霉素氨基糖苷（PAN）诱导的肾病大鼠模型中足细胞的影响。大鼠被分配到对照、PAN肾病和托伐普坦治疗的PAN肾病组（n = 9/组）。在第10天测量尿蛋白排泄和血清总蛋白、白蛋白、肌酐和总胆固醇水平。通过免疫荧光和电子显微镜检查托伐普坦对肾组织中足细胞的影响。PAN在第10天诱导大量蛋白尿和血清肌酐升高，托伐普坦可显著改善这两种情况。足细胞相关蛋白nephrin和podocin的免疫荧光研究显示PAN肾病大鼠颗粒染色模式。在托伐普坦治疗的大鼠中，nephrin和podocin表达保留了正常的线性模式。电镜显示托伐普坦治疗大鼠足突消失得到改善。托伐普坦对PAN肾病足细胞损伤和蛋白尿具有保护作用。这项研究表明，托伐普坦通过影响PAN肾病中足细胞的形态和可能的功能发挥肾保护作用。托伐普坦是治疗肾水肿的一种有前途的药理学工具。
Proteinuria caused by glomerular disease is characterized by podocyte injury. Vasopressin V2 receptor antagonists are effective in reducing albuminuria, although their actions on glomerular podocytes have not been explored. The objective of this study was to evaluate the effects of tolvaptan, a selective oral V2 receptor antagonist, on podocytes in a puromycin aminonucleoside (PAN)-induced nephrosis rat model.Rats were allocated to a control, PAN nephrosis, or tolvaptan-treated PAN nephrosis group (n = 9 per group). Urinary protein excretion and serum levels of total protein, albumin, creatinine, and total cholesterol were measured on day 10. The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy.PAN induced massive proteinuria and serum creatinine elevation on day 10, both of which were significantly ameliorated by tolvaptan. Immunofluorescence studies of the podocyte-associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats. In tolvaptan-treated rats, nephrin and podocin expressions retained their normal linear pattern. Electron microscopy showed foot process effacement was ameliorated in tolvaptan-treated rats.Tolvaptan is protective against podocyte damage and proteinuria in PAN nephrosis. This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis. Tolvaptan is a promising pharmacological tool in the treatment of renal edema.