Inhibition of NF-κB-dependent Bcl-xL expression by clusterin promotes albumin-induced tubular cell apoptosis
Inhibition of NF-κB-dependent Bcl-xL expression by clusterin promotes albumin-induced tubular cell apoptosis
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DOI：
10.1038/sj.ki.5002563
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发表时间：
2008-03-01
影响因子：
19.6
通讯作者：
Quigg, R. J.
中科院分区：
文献类型：
--
作者：
Takase, O.;Minto, A. W. M.;Quigg, R. J.
细胞凋亡和炎症是慢性肾脏疾病进展的重要因素，可受丛生蛋白（一种调节细胞凋亡的分泌性糖蛋白）和核因子-κ B（NF-κ B，一种修饰炎性基因表达的转录因子）的影响。我们研究了蛋白尿引起的肾脏疾病及其对聚集蛋白介导的细胞凋亡的影响。暴露于牛血清白蛋白（BSA）培养的小鼠近端小管上皮细胞的NF-κ B和激活蛋白-1（AP-1）的激活导致在数小时内，随后在其激活下降，细胞外信号调节激酶（ERK 1/2）的激活减少，减少细胞相关的抗凋亡Bcl-xL蛋白，但增加凋亡。在3天的时间段内，培养基中的白藜芦醇逐渐增加。干扰素siRNA阻断蛋白质产生，增加NF-κ B活化，并显著增加细胞Bcl-xL蛋白，从而减少自发和BSA诱导的细胞凋亡。针对NF-κ B抑制剂I κ B α的siRNA具有类似的结果。BSA刺激的NF-κ B活化通过阻止ERK 1/2磷酸化而间接降低AP-1活性。这些体外研究表明，丛生蛋白抑制NF-κ B介导的抗凋亡作用的明显稳定的I κ B α转换从促进炎症细胞凋亡蛋白尿。
Apoptosis and inflammation, important contributors to the progression of chronic kidney disease, can be influenced by clusterin ( a secreted glycoprotein that regulates apoptosis) and nuclear factor-kappa B (NF-kappa B, a transcription factor modifying the expression of inflammatory genes). We studied proteinuria-induced renal disease and its influence on clusterin-mediated apoptosis. Exposure of cultured mouse proximal tubule epithelial cells to bovine serum albumin (BSA) resulted in activation of NF-kappa B and activator protein-1 (AP-1) within hours followed by a decline in their activation, decreased activation of extracellular signal-regulated kinases (ERK1/2), decreased cell-associated antiapoptotic Bcl-xL protein but increased apoptosis. Clusterin progressively increased in the media over a 3 day period. Clusterin siRNA blocked protein production, increased NF-kappa B activation, and significantly increased cellular Bcl-xL protein, thereby reducing spontaneous and BSA-induced apoptosis. An siRNA to the NF-kappa B inhibitor I kappa B alpha had similar results. BSA-stimulated NF-kappa B activation reciprocally decreased AP-1 activity by preventing ERK1/2 phosphorylation. These in vitro studies suggest that clusterin inhibits NF-kappa B-mediated antiapoptotic effects by the apparent stabilization of I kappa B alpha switching from promoting inflammation to apoptosis during proteinuria.