Caspase inhibition reduces tubular apoptosis and proliferation and slows disease progression in polycystic kidney disease
Caspase inhibition reduces tubular apoptosis and proliferation and slows disease progression in polycystic kidney disease
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DOI：
10.1073/pnas.0408518102
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发表时间：
2005-05-10
影响因子：
11.1
通讯作者：
Edelstein, CL
中科院分区：
文献类型：
--
作者：
Tao, YX;Kim, J;Edelstein, CL
我们之前已经证明患有多囊肾病 (PKD) 的 Han:SPRD 大鼠肾脏中促凋亡 caspase-3 增加。本研究的目的是确定半胱天冬酶抑制对 Han:SPRD PKD 大鼠模型中肾小管细胞凋亡和增殖、囊肿形成和肾衰竭的影响。杂合子 (Cy/+) 和同窝对照 (+/+) 雄性大鼠在 3 周龄断奶，然后通过 Alzet (Palo Alto, CA) 微型泵或载体 [聚乙二醇 (PEG 300)] 使用 caspase 抑制剂 IDN-8050（每天 10 mg/kg）治疗 5 周。与+/+大鼠相比，Cy/+大鼠的双肾/总体重比增加了一倍多。 IDN-8050 使 Cy/+ 大鼠的肾脏肿大显着减少 44%，囊肿体积密度减少 29%。患有 PKD 的 Cy/+ 大鼠患有肾衰竭，表现为血液尿素氮显着增加。 IDN-8050 显着降低 Cy/+ 大鼠血尿素氮的增加。与媒介物处理的 Cy/+ 大鼠相比，IDN-8050 处理的 Cy/+ 大鼠中非囊性小管和囊性小管中增殖细胞核抗原阳性肾小管细胞和凋亡肾小管细胞的数量显着减少。免疫印迹显示，与媒介物处理的 Cy/+ 大鼠相比，IDN-8050 处理的 Cy/+ 大鼠中 caspase-3 (20 kDa) 的活性形式显着降低。总之，在 PKD 大鼠模型中，IDN-8050 抑制 caspase (i) 减少囊性小管和非囊性小管的细胞凋亡和增殖； (ii) 抑制肾脏增大和囊肿发生，以及 (iii) 减轻肾功能的丧失。
We have previously demonstrated an increase in proapoptotic caspase-3 in the kidney of Han:SPRD rats with polycystic kidney disease (PKD). The aim of the present study was to determine the effect of caspase inhibition on tubular cell apoptosis and proliferation, cyst formation, and renal failure in the Han:SPRD rat model of PKD. Heterozygous (Cy/+) and littermate control (+/+) male rats were weaned at 3 weeks of age and then treated with the caspase inhibitor IDN-8050 (10 mg/kg per day) by means of an Alzet (Palo Alto, CA) minipump or vehicle [polyethylene glycol (PEG 300)] for 5 weeks. The two-kidney/total body weight ratio more than doubled in Cy/+ rats compared with +/+ rats. IDN-8050 significantly reduced the kidney enlargement by 44% and the cyst volume density by 29% in Cy/+ rats. Cy/+ rats with PKD have kidney failure as indicated by a significant increase in blood urea nitrogen. IDN-8050 significantly reduced the increase in blood urea nitrogen in the Cy/+ rats. The number of proliferating cell nuclear antigen-positive tubular cells and apoptotic tubular cells in non- cystic and cystic tubules was significantly reduced in IDN-8050-treated Cy/+ rats compared with vehicle-treated Cy/+ rats. On immunoblot, the active form of caspase-3 (20 kDa) was significantly decreased in IDN-8050-treated Cy/+ rats compared with vehicle-treated Cy/+ rats. In summary, in a rat model of PKD, caspase inhibition with IDN-8050 (i) decreases apoptosis and proliferation in cystic and noncystic tubules; (ii) inhibits renal enlargement and cystogenesis, and (iii) attenuates the loss of kidney function.