Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1
Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1
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DOI：
10.1093/hmg/ddn039
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发表时间：
2008-06-01
影响因子：
3.5
通讯作者：
Somlo, Stefan
中科院分区：
文献类型：
--
作者：
Shibazaki, Sekiya;Yu, Zhiheng;Somlo, Stefan
多囊肾病（ADPKD）是由于多囊蛋白-1或-2丢失后肾脏无法正确维持三维结构所致。在胚胎发育过程中，肾脏选择性失活Pkd 1的小鼠发展为严重的肾囊肿，并在出生后3周内死于肾衰竭。在该模型中，包囊仅由Cre重组酶具有活性的细胞形成，但包囊扩张的表观速度因片段和细胞类型而异。尽管出生后至少21天存在纤毛，但嵌入细胞不参与囊肿扩张。囊性节段显示出持续增加的增殖所确定的溴脱氧尿苷（BrdU）掺入，然而，绝对增殖指数是依赖于潜在的肾小管细胞的增殖潜力。细胞外调节激酶（MAPK/ERK）途径的组分从Ras通过MEK 1/2和ERK 1/2到效应物P90（RSK）在围产期Pkd 1和成人Pkd 2直系同源基因疾病模型中都被激活。MAPK/ERK激活的模式是局灶性的，并且与通过BrdU摄取鉴定的活跃增殖的模式不相关。使用MEK 1/2抑制剂U 0126在ADPKD急性围产期Pkd 1模型中评估ERK 1/2激活和囊肿细胞增殖之间因果关系的可能性。在该模型中，U 0126处理在足以减少囊性肾中磷酸化ERK 1/2的剂量下对囊肿形成的进展没有影响。ADPKD中的囊肿表现出增殖和MAPK/ERK活化的增加，但抑制ERK 1/2活化不能阻止囊肿生长。
Polycystic kidney disease (ADPKD) results from failure of the kidney to properly maintain three-dimensional structure after loss of either polycystin-1 or -2. Mice with kidney selective inactivation of Pkd1 during embryogenesis develop profound renal cystic disease and die from renal failure within 3 weeks of birth. In this model, cysts form exclusively from cells in which Cre recombinase is active, but the apparent pace of cyst expansion varies by segment and cell type. Intercalated cells do not participate in cyst expansion despite the presence of cilia up to at least postnatal day 21. Cystic segments show a persistent increase in proliferation as determined by bromodeoxyuridine (BrdU) incorporation; however, the absolute proliferative index is dependent on the underlying proliferative potential of kidney tubule cells. Components of the extracellular regulated kinase (MAPK/ERK) pathway from Ras through MEK1/2 and ERK1/2 to the effector P90(RSK) are activated in both perinatal Pkd1 and adult Pkd2 ortholgous gene disease models. The pattern of MAPK/ERK activation is focal and does not correlate with the pattern of active proliferation identified by BrdU uptake. The possibility of a causal relationship between ERK1/2 activation and cyst cell proliferation was assessed in vivo in the acute perinatal Pkd1 model of ADPKD using MEK1/2 inhibitor U0126. U0126 treatment had no effect on progression of cyst formation in this model at doses sufficient to reduce phospho-ERK1/2 in cystic kidneys. Cysts in ADPKD exhibit both increased proliferation and activation of MAPK/ERK, but cyst growth is not prevented by inhibition of ERK1/2 activation.