Preventive and therapeutic effects of imatinib in Wistar-Kyoto rats with anti-glomerular basement membrane glomerulonephritis
Preventive and therapeutic effects of imatinib in Wistar-Kyoto rats with anti-glomerular basement membrane glomerulonephritis
复制标题
DOI：
10.1038/ki.2009.43
复制
发表时间：
2009-05-01
影响因子：
19.6
通讯作者：
Akizawa, Tadao
中科院分区：
文献类型：
--
作者：
Iyoda, Masayuki;Shibata, Takanori;Akizawa, Tadao
伊马替尼是一种选择性酪氨酸激酶抑制剂，可以阻断血小板衍生生长因子受体（PDGFR）的活性，并对各种细胞类型具有免疫调节作用。在这里，我们测量了伊马替尼对Wistar-Kyoto肾毒性血清肾炎大鼠的保护作用，这是一种CD8+ T细胞和巨噬细胞发挥致病作用的肾脏疾病模型。各组动物从肾炎诱导前1天至诱导后13天以及诱导疾病后第7天至第20天给予伊马替尼。与对照组相比，伊马替尼治疗各组大鼠各时间点蛋白尿明显减少，血清尿素氮和肌酐明显降低，肾小球坏死、月牙状、纤维蛋白沉积数量明显减少。伊马替尼治疗的大鼠肾小球巨噬细胞积累显著减少，肾皮质pdgfr - β和M-CSF受体mRNA表达显著降低。通过共定位，我们发现肾小球巨噬细胞降低了IL-1 β和MCP-1蛋白的表达。晚期伊马替尼治疗可显著降低蛋白尿、血清尿素氮和肌酐，并逆转肾脏组织病理改变。我们表明伊马替尼具有肾保护和治疗特性，并提供临床前工作，需要在新月状肾小球肾炎患者中得到证实。
Imatinib is a selective tyrosine kinase inhibitor that can block activity of the platelet-derived growth factor receptor (PDGFR) and that has immunomodulatory effects on various cell types. Here we measured the protective effects of imatinib in Wistar-Kyoto rats with nephrotoxic serum nephritis, a kidney disease model where CD8+ T cells and macrophages play pathogenetic roles. Groups of animals were given imatinib from one day before up to 13 days following induction of nephritis and from day 7 to 20 following disease induction. Compared to control rats, at each time point imatinib treatment caused significantly less proteinuria, lowered serum blood urea nitrogen and creatinine, and decreased the number of glomeruli with necrosis, crescents, and fibrin deposits. Imatinib-treated rats had a significant reduction in glomerular macrophage accumulation and reduced renal cortical PDGFR-beta and M-CSF receptor mRNA expression. Using colocalization we found that glomerular macrophages had reduced IL-1 beta and MCP-1 protein expression. Late imatinib treatment significantly reduced proteinuria, serum blood urea nitrogen, and creatinine, and reversed renal histopathological changes. We show that imatinib has renoprotective and therapeutic properties and provide pre-clinical work that will need to be confirmed in patients with crescentic glomerulonephritis.