PPAR-α激动剂对PAN诱导肾小球足细胞损伤的保护作用

摘要

Aim To investigate the function of fenofi-brate on PAN ( puromycin aminonucleoside )-induced podocyte injury. Methods SD female rats of 18-week-old were randomly assigned into 3 groups ( n =6 ) . Mice in PAN group and fenofibrate treated group received a single intravenous injection of PAN ( 65 mg ·kg-1 ) , while those in control group received equal volume of saline. Mice in fenofibrate treated group re-ceived 40 mg · kg-1 · d-1 of fenofibrate ( intragastric administration ) on day 1 after PAN injection , while those in PAN group and control group received equal volume of vehicle. 24 hours urine samples from all group were collected on day 0(1 day before PAN injec-tion), day 6, day 10. The 24 hours urine protein was detected by Bradford assay. All the rats were sacrificed 10 days after the induction of podocyte injury, and glo-merulus sample were collected. The expression of podocyte injury marker and transcription level in apop-tosis, podocyte cytoskeleton protein, slit diaphragm protein were evaluated by Western blot and real-time PCR. Results Compared with the control group, 10 days after injection of PAN, 24 hours urine protein was obviously increased, and the expression and transcrip-tion level of podocyte injury marker desmin, apoptosis, podocyte cytoskeleton protein, slit diaphragm protein were upregulated greatly, however, those were signifi-cantly lower in fenofibrate treated group as compared with those in PAN group. Conclusions PPAR-α ago-nist fenofibrate can ameliorate PAN-induced glomerulus podocyte injury, and the mechanism involved may be associated with inhibition of the mitochondria apopto-sis, TGF-β/Smad pathway and p38 pathway.%目的：探讨PPAR-α激动剂非诺贝特对氨基核苷嘌呤霉素( PAN )诱导肾小球足细胞损伤的作用及其机制。方法将18只8周龄SD ♀大鼠随机分为3组( n=6)。 PAN模型组和非诺贝特组1次尾静脉注射PAN 65 g·g-1,空白对照组注射生理盐水,PAN注射后d 1,非诺贝特组灌胃非诺贝特40 mg·kg-1·d-1),空白对照组和PAN模型组灌胃等体积溶剂。分别于d 0、6、10收集24 h尿样,采用Bradford法测定大鼠24 h尿蛋白含量。 PAN注射后10 d将大鼠安乐死,收集肾小球样本。利用Western blot和Real-Time PCR检测肾小球足细胞损伤标记物的表达和凋亡相关基因、骨架蛋白以及裂隙膜蛋白基因转录活性。结果注射 PAN 后 d 10,24 h 尿蛋白含量较 d 0明显上升,足细胞损伤标记物desmin基因水平和蛋白表达明显增加,线粒体凋亡通路、TGF-β/Smad通路和p38通路转录水平明显上调,足细胞骨架蛋白和裂隙膜蛋白的转录活性明显增加。非诺贝特处理能够明显降低PAN引起的尿蛋白,改善PAN对足细胞的损伤作用；明显抑制凋亡通路的转录活性；降低骨架蛋白和裂隙膜蛋白的转录活性。结论非诺贝特能够改善PAN诱导的肾小球足细胞损伤,其作用机制与抑制凋亡通路有关。