In vitro modulation of cyst formation by a novel tyrosine kinase inhibitor.
In vitro modulation of cyst formation by a novel tyrosine kinase inhibitor.
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DOI：
10.1046/j.1523-1755.1999.00577.x
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发表时间：
1999-08
影响因子：
19.6
通讯作者：
W. Sweeney;L. Futey;P. Frost;E. Avner
中科院分区：
文献类型：
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作者：
W. Sweeney;L. Futey;P. Frost;E. Avner
在许多小鼠模型中，隐性传播多囊肾病（PKD）的特征是最初形成近端小管囊肿（1期），随后是肾集小管囊肿（CT）的生长和扩大（2期）。先前的研究报道了利用胚胎肾外植体和新生肾外植体微片进行器官培养，可以在体外操纵1期囊肿的形成和生长。方法在Transwell组织培养插入物上培养出生后肾脏显微切片，对2期CT囊肿的发育和生长进行实验操作。该系统用于测试治疗PKD的潜在治疗化合物。这种化合物EKI-785通过抑制表皮生长因子受体（EGFR）自磷酸化来调节CT囊肿中表皮生长因子受体（EGFR）表达的改变。结果这些研究表明：(a)对先前描述的器官培养系统进行微小修改，可以成功培养更成熟的肾组织；(b)与EGF和EKI-785处理的囊性外植体相比，EGF和EKI-785处理的囊性外植体在CT上的囊性病变明显减少。结论本研究提示，药物策略可降低小鼠PKD的EGFR酪氨酸激酶活性和CT囊肿的形成和扩大。
BACKGROUND Recessively transmitted polycystic kidney disease (PKD) in many murine models is characterized by the initial formation of proximal tubular cysts (stage 1), followed by growth and enlargement of renal collecting tubule (CT) cysts (stage 2). Previous studies have reported that stage 1 cyst formation and growth could be manipulated in vitro by using embryonic kidney explants and newborn explant microslices in organ culture. METHODS Microslices of postnatal kidneys cultured on Transwell tissue culture inserts allow experimental manipulation of stage 2 CT cyst development and growth. This system was used to test a potential therapeutic compound for treatment of PKD. This compound, EKI-785, modulates altered epidermal growth factor receptor (EGFR) expression in CT cysts by inhibition of EGFR autophosphorylation. RESULTS These studies demonstrate that: (a) minor modifications of the previously described organ culture system permit successful culture of more mature renal tissue, and (b) cystic explants treated with EGF and EKI-785 demonstrated a marked reduction in CT cystic lesions compared with cystic explants treated with EGF alone. CONCLUSIONS This study suggests that pharmacological strategies can be used to decrease EGFR tyrosine kinase activity and CT cyst formation and enlargement in murine PKD.