c-myc antisense oligonucleotide treatment ameliorates murine ARPKD.
c-myc antisense oligonucleotide treatment ameliorates murine ARPKD.
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DOI：
10.1046/j.1523-1755.2002.0610s1125.x
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发表时间：
2002
影响因子：
19.6
通讯作者：
J. Ricker;J. Mata;P. Iversen;V. Gattone
中科院分区：
文献类型：
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作者：
J. Ricker;J. Mata;P. Iversen;V. Gattone
c-myc的过表达被认为在多囊肾病（PKD）的发病机制中发挥作用。c-myc在所有啮齿类动物的PKD模型以及人类ADPKD中表达增加。为了确定肾c-myc的过度表达是否与肾囊肿的形成有关，我们用c-myc mRNA的反义寡聚物（ASO）处理C57BL/6J-cpk幼崽（ARPKD的动物模型）。方法C57BL/6J-cpk窝仔在出生后7 ~ 20天注射30 mg c-myc ASO。对照组小鼠接受假注射或等量的打乱ASO注射。第20天，测定肾重、体重、血清尿素氮（SUN）、红细胞压积、ASO肾浓度。在肾脏中，用免疫印迹法检测c-Myc和PCNA蛋白，用northern印迹杂交法检测肾中c-Myc、EGF、SGP-2和组蛋白H4的稳态水平。免疫组化法定位c-Myc和PCNA蛋白。结果：与假手术和加药ASO对照组相比，经c-myc ASO治疗的囊性小鼠肾脏相对重量降低，肾功能改善，囊性改变量减少。c-myc反义处理可部分逆转几种PKD相关蛋白和mrna的异常表达。非囊性小管中C-myc染色减少。用c-myc ASO治疗没有引起红细胞压积或总体重的降低，这表明有益效果不是由于快速生长组织中细胞增殖的普遍抑制。结论c-Myc可能在cpk诱导的小鼠PKD的膀胱形成中起作用，反义靶向c-Myc的过表达部分改善了肾脏的改变。
BACKGROUND Overexpression of c-myc is postulated to play a role in the pathogenesis of polycystic kidney disease (PKD). c-myc expression is increased in all rodent models of PKD that have been examined as well as in human ADPKD. To determine whether overexpression of renal c-myc contributes to renal cyst formation, C57BL/6J-cpk litters (an animal model of ARPKD) were treated with an antisense oligomer (ASO) to c-myc mRNA. METHODS Injections of 30 microg of a c-myc ASO were given to C57BL/6J-cpk litters on postnatal days 7-20. Control mice received either sham injections or injections of an equal amount of a scrambled ASO. At 20 days, kidney weight, body weight, serum urea nitrogen (SUN), hematocrit, and renal concentration of ASO were determined. In kidney, c-Myc and PCNA protein were assessed by immunoblotting and steady state levels of renal RNA for c-myc, EGF, SGP-2, and histone H4 were assessed by northern blot hybridization. c-Myc and PCNA proteins were localized by immunohistochemistry. RESULTS Cystic mice treated with the c-myc ASO had a decreased relative kidney weight, improved renal function, and a reduced amount of cystic change compared with sham and scrambled ASO controls. The abnormal expression of several PKD related proteins and mRNAs were partially reversed by c-myc antisense treatment. c-myc staining appeared to be reduced in the noncystic tubules. Treatment with the c-myc ASO did not cause a reduction in hematocrit or total body weight indicating that the beneficial effects were not due to a generalized inhibition of cell proliferation in rapidly growing tissue. CONCLUSIONS c-Myc appears to play a role in the cystogenesis of cpk-induced murine PKD and antisense targeting the overexpression of c-myc partially ameliorated the renal changes.