ER stress contributes to renal proximal tubule injury by increasing SREBP-2-mediated lipid accumulation and apoptotic cell death
ER stress contributes to renal proximal tubule injury by increasing SREBP-2-mediated lipid accumulation and apoptotic cell death
复制标题
DOI：
10.1152/ajprenal.00482.2011
复制
发表时间：
2012-07-01
影响因子：
4.2
通讯作者：
Austin, Richard C.
中科院分区：
文献类型：
--
作者：
Lhotak, Sarka;Sood, Sudesh;Austin, Richard C.
洛塔克·S，苏德·S，布里布尔·E，卡莱尔·雷，科尔根·SM，马泽蒂·A，迪克豪特，英格拉姆·AJ，奥斯汀·RC内质网应激通过增加SREBP-2介导的脂质堆积和细胞凋亡而导致肾近端小管损伤。AM J Physiol Renal Physiol 303：F266-F278,2012。2012年5月9日首次出版；DOI：10.1152/ajprenal.00482.2011。-肾近端小管损伤是由已知引起内质网(ER)应激的药物/条件引起的，包括具有肾毒性作用的免疫抑制药物环孢素A(CsA)。然而，内质网应激促进近端小管细胞损伤的潜在机制尚不清楚。在这项研究中，我们报告了使用经典ER应激源衣霉素(TM)处理的小鼠或显示CsA诱导肾毒性的人肾活检标本中的脂质积累、固醇调节元件结合蛋白-2(SREBP-2)表达和肾脏近端小管的ER应激。内质网应激标志物[78 kDa葡萄糖调节蛋白(GRP78)，CHOP]与SREBP-2的表达和脂质堆积在TM或CsA暴露的近端小管细胞内显著共存。长时间的内质网应激导致富脂近端小管细胞凋亡增加，GRP78、SREBP-2和具有促凋亡特性的SREBP-2诱导基因GRP78、SREBP-2和钙非依赖性磷脂酶A(2)(IPLA2)共定位。在培养的HK-2人近端小管细胞中，CsA和TM诱导的内质网应激导致脂质堆积和SREBP-2激活。此外，在HK-2细胞中过表达SREBP-2或激活内源性SREBP-2可刺激细胞凋亡。用1位丝氨酸蛋白酶抑制剂AEBSF抑制SREBP-2的激活可阻止内质网应激诱导的脂质堆积和细胞凋亡。内质网驻留伴侣GRP78的过表达可减轻内质网应激，并抑制CsA诱导的SREBP-2表达和脂质积累。综上所述，我们的研究结果表明，内质网应激诱导的SREBP-2激活通过调节脂质稳态参与了肾近端小管细胞损伤。
Lhotak S, Sood S, Brimble E, Carlisle RE, Colgan SM, Mazzetti A, Dickhout JG, Ingram AJ, Austin RC. ER stress contributes to renal proximal tubule injury by increasing SREBP-2-mediated lipid accumulation and apoptotic cell death. Am J Physiol Renal Physiol 303: F266-F278, 2012. First published May 9, 2012; doi:10.1152/ajprenal.00482.2011.-Renal proximal tubule injury is induced by agents/conditions known to cause endoplasmic reticulum (ER) stress, including cyclosporine A (CsA), an immunosuppressant drug with nephrotoxic effects. However, the underlying mechanism by which ER stress contributes to proximal tubule cell injury is not well understood. In this study, we report lipid accumulation, sterol regulatory element-binding protein-2 (SREBP-2) expression, and ER stress in proximal tubules of kidneys from mice treated with the classic ER stressor tunicamycin (Tm) or in human renal biopsy specimens showing CsA-induced nephrotoxicity. Colocalization of ER stress markers [78-kDa glucose regulated protein (GRP78), CHOP] with SREBP-2 expression and lipid accumulation was prominent within the proximal tubule cells exposed to Tm or CsA. Prolonged ER stress resulted in increased apoptotic cell death of lipid-enriched proximal tubule cells with colocalization of GRP78, SREBP-2, and Ca2+-independent phospholipase A(2) (iPLA(2)beta), an SREBP-2 inducible gene with proapoptotic characteristics. In cultured HK-2 human proximal tubule cells, CsA- and Tm-induced ER stress caused lipid accumulation and SREBP-2 activation. Furthermore, overexpression of SREBP-2 or activation of endogenous SREBP-2 in HK-2 cells stimulated apoptosis. Inhibition of SREBP-2 activation with the site-1-serine protease inhibitor AEBSF prevented ER stress-induced lipid accumulation and apoptosis. Overexpression of the ER-resident chaperone GRP78 attenuated ER stress and inhibited CsA-induced SREBP-2 expression and lipid accumulation. In summary, our findings suggest that ER stress-induced SREBP-2 activation contributes to renal proximal tubule cell injury by dysregulating lipid homeostasis.