Caspase-3 gene deletion prolongs survival in polycystic kidney disease
Caspase-3 gene deletion prolongs survival in polycystic kidney disease
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DOI：
10.1681/asn.2006121378
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发表时间：
2008-04-01
影响因子：
13.6
通讯作者：
Edelstein, Charles L.
中科院分区：
文献类型：
--
作者：
Tao, Yunxia;Zafar, Iram;Edelstein, Charles L.
在多囊肾病（PKD）大鼠模型中，泛半胱天冬酶抑制剂减少肾小管细胞凋亡和增殖并减缓疾病进展。然而，目前尚不清楚哪些特定的半胱天冬酶参与PKD进展。由于半胱天冬酶-3是细胞凋亡的主要介质，因此确定了其在常染色体隐性PKD中的作用。将caspase-3基因缺失的小鼠与先天性多囊肾（cpk）突变小鼠杂交，产生双突变小鼠。cpk; casp 3（-/-）小鼠的寿命几乎是同窝对照cpk小鼠的4倍（平均存活期为117天对32天，P < 0.01），cpk; casp 3（+/-）小鼠的寿命略长于对照（平均存活期为56天）。此外，cpk; Casp 3（-/-）小鼠的肾脏重量（相对于体重）显著低于cpk和cpk; Casp 3（+/-）小鼠。尽管缺失半胱天冬酶-3，然而，细胞凋亡发生和囊肿形成，因此，在囊性肾细胞凋亡的替代途径进行了研究。与野生型对照组相比，在cpk、cpk; Casp 3（+/-）和cpk; Casp 3（-/-）小鼠中，Caspase-7上调，抗凋亡蛋白BcI-2下调。总之，caspase-3的纯合缺失显著降低了cpk小鼠的存活率，但caspase-7介导的通路可能弥补了功能性caspase-3的缺失。这些发现表明，泛半胱天冬酶抑制剂可能比选择性半胱天冬酶抑制剂在PKD中具有更大的治疗效果。
Pan-caspase inhibition reduces tubular apoptosis and proliferation and slows progression of disease in a rat model of polycystic kidney disease (PKD). It is unknown, however, which specific caspases are involved in PKD progression. Because caspase-3 is a major mediator of apoptosis, its role in autosomal recessive PKD was determined. Mice with caspase-3 gene deletion were crossed with mice harboring the congenital polycystic kidney (cpk) mutation to generate double-mutant mice. cpk;casp3(-/-) mice lived nearly 4 times longer than littermate control cpk mice (mean survival of 117 d versus 32 d, P < 0.01), and cpk;casp3(+/-) mice lived slightly longer than controls (mean survival of 56 d). In addition, the kidney weight, relative to body weight, was significantly lower in the cpk;casp3(-/-) mice than in the cpk and cpk;casp3(+/-) mice. Despite deletion of caspase-3, however, apoptosis occurred and cysts formed; therefore, the alternative pathways of apoptosis in cystic kidneys were investigated. Caspase-7 was up-regulated and the anti-apoptotic protein BcI-2 was down-regulated in cpk, cpk;casp3(+/-), and cpk;casp3(-/-) mice compared with wild-type controls. In summary, homozygous deletion of caspase-3 markedly prolongs survival of cpk mice, but a caspase-7-mediated pathway may compensate for the deficiency of functional caspase-3. These findings suggest that pan-caspase inhibition may have a greater therapeutic effect than selective caspase inhibition in PKD.