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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Caspase inhibition reduces tubular apoptosis and proliferation and slows disease progression in polycystic kidney disease
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Caspase inhibition reduces tubular apoptosis and proliferation and slows disease progression in polycystic kidney disease

机译：Caspase抑制作用减少多囊肾疾病中的肾小管凋亡和增殖并减缓疾病进展

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摘要

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.
机译：我们以前已经证明患有多囊性肾病（PKD）的Han：SPRD大鼠肾脏中促凋亡的caspase-3增加。本研究的目的是确定caspase抑制对PKD的Han：SPRD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（Cy / +）和同窝对照（+ / +）雄性大鼠在3周龄时断奶，然后通过半胱氨酸蛋白酶抑制剂IDN-8050（每天10 mg / kg）通过Alzet（Palo Alto， CA）微型泵或溶媒[聚乙二醇（PEG 300）]持续5周。与+ / +大鼠相比，Cy / +大鼠的两个肾脏/总体重比增加了一倍以上。 IDN-8050在Cy / +大鼠中使肾脏肿大明显减少了44％，囊肿体积密度减少了29％。 Cy / + PKD大鼠患有肾衰竭，如血尿素氮显着增加所表明。 IDN-8050显着降低了Cy / +大鼠血液中尿素氮的增加。与载体治疗的Cy / +大鼠相比，IDN-8050治疗的Cy / +大鼠的非囊性和囊性小管中增殖细胞核抗原阳性小管和凋亡小管的数量明显减少。在免疫印迹上，与媒介物处理的Cy / +大鼠相比，在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，用IDN-8050（ⅰ）抑制胱天蛋白酶可减少囊性和非囊性小管的凋亡和增殖。 （ⅱ）抑制肾脏肿大和囊肿形成，（ⅲ）减轻肾功能的丧失。

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