Statins prevent oxidized LDL-induced injury of glomerular podocytes by activating the phosphatidylinositol 3-kinase/AKT-signaling pathway
Statins prevent oxidized LDL-induced injury of glomerular podocytes by activating the phosphatidylinositol 3-kinase/AKT-signaling pathway
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DOI：
10.1681/asn.2004080629
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发表时间：
2005-07-01
影响因子：
13.6
通讯作者：
Camussi, G
中科院分区：
文献类型：
--
作者：
Bussolati, B;Deregibus, MC;Camussi, G
足细胞的损伤与肾小球对蛋白质的大小选择性屏障的改变有关。在本研究中，氧化LDL （oxLDL）而非天然LDL诱导人培养足细胞凋亡，并降低Akt活性和P-Akt/Akt比值。此外，氧化低密度脂蛋白诱导肾小球狭缝隔膜特异性黏附分子肾素的重新分布和损失。在Nephrin减少之前，抑制了Nephrin酪氨酸磷酸化及其与p85磷脂酰肌醇3-激酶（PI3K）的关联。此外，三种不同的他汀类药物，美伐他汀、普伐他汀和辛伐他汀，通过刺激Akt活性，以剂量依赖性的方式抑制oxLDL诱导的细胞凋亡和nephrin丢失。此外，辛伐他汀显著增加足细胞nephrin蛋白和mRNA的表达。他汀类药物的保护作用被两种不相关的PI3K药物抑制剂LY294002和wortmannin治疗足细胞阻断，这表明PI3K起作用，而甲羟戊酸则表明依赖于HMG-CoA还原酶活性。他汀类药物直接刺激Akt磷酸化和活性。最后，oxLDL诱导培养足细胞收缩，并增加白蛋白在其单层中的扩散，这被他汀类药物抑制。综上所述，他汀类药物可减少氧化低密度脂蛋白诱导的肾小球足细胞凋亡和肾素的丢失。他汀类药物诱导的Akt活化可能通过抑制其再分配和脱落以及刺激其合成来防止肾素的丢失。这些数据为他汀类药物的抗蛋白尿作用提供了理论依据。
The injury of podocytes is associated with alterations of the glomerular size-selective barrier to proteins. In this study, oxidized LDL (oxLDL) but not native LDL induced apoptosis in human cultured podocytes and reduced Akt activity and P-Akt/Akt ratio. Moreover, oxLDL-induced redistribution and loss of nephrin, an adhesion molecule specific for the glomerular slit diaphragm. Nephrin reduction was preceded by inhibition of nephrin tyrosine phosphorylation and of its association with p85 phosphatidylinositol 3-kinase (PI3K). Moreover, three different statins, mevastatin, pravastatin, and simvastatin, inhibited in a dose-dependent manner apoptosis and loss of nephrin induced by oxLDL by stimulating Akt activity. In addition, simvastatin significantly increased the expression of nephrin protein and mRNA by podocytes. The protective effects of statins were blocked by treatment of podocytes with two unrelated pharmacologic inhibitors of PI3K, LY294002 and wortmannin, suggesting a role for PI3K, and by mevalonate, indicating dependency on HMG-CoA reductase activity. Statins directly stimulated Akt phosphorylation ad activity. Finally, oxLDL induced a retraction of cultured podocytes and an increase in the albumin diffusion across their monolayer that was inhibited by treatment with statins. In conclusion, statins reduced the oxLDL-induced apoptosis and loss of nephrin in glomerular podocytes. The statin-induced Akt activation may protect from the loss of nephrin by an inhibition of its redistribution and shedding and by a stimulation of its synthesis. These data provide a rationale for the anti-proteinuric effect of statins.