Intrarenal renin-angiotensin system mediates fatty acid-induced ER stress in the kidney
Intrarenal renin-angiotensin system mediates fatty acid-induced ER stress in the kidney
复制标题
肾内肾素-血管紧张素系统介导脂肪酸诱导的肾脏内质网应激。
DOI：
10.1152/ajprenal.00223.2015
复制
发表时间：
2016-03-01
影响因子：
4.2
通讯作者：
Wang, Weidong
中科院分区：
文献类型：
--
作者：
Li, Chunling;Lin, Yu;Wang, Weidong
肥胖相关的肾脏疾病与促进有害细胞反应的热量过剩有关。饱和游离脂肪酸在小管细胞中的积累会产生脂肪毒性，包括显著的细胞功能障碍和损伤。本研究的目的是阐明肾素-血管紧张素系统（RAS）激活在培养的人近端小管上皮细胞（HK2）和高脂饮食小鼠饱和脂肪酸诱导的内质网（ER）应激中的作用。饱和脂肪酸棕榈酸（PA; 0.8 mM）处理24h诱导HK2内质网应激，导致未折叠蛋白反应，免疫印迹检测显示内质网伴侣结合免疫球蛋白蛋白（BiP）和促凋亡转录因子C/EBP同源蛋白（CHOP）蛋白表达增加。PA处理还诱导肌醇需要蛋白1α (IRE1α)、磷酸化真核起始因子-α (eIF2α)和激活转录因子4 （ATF4）的蛋白表达增加以及caspase-3的激活。PA处理与培养培养基中血管紧张素II水平升高相关。血管紧张素II型1受体（AT1R）阻滞剂缬沙坦或肾素抑制剂aliskiren可显著抑制pa诱导的HK2细胞中BiP、CHOP、IRE1α、p-eIF2α和ATF4的上调。相比之下，缬沙坦或阿力克伦不能预防肾霉素引起的内质网应激。高脂喂养14周的C57BL/6小鼠与对照小鼠相比，BiP和CHOP蛋白表达增加，缬沙坦治疗显著减弱。与对照组相比，高脂饮食小鼠血清和尿液中的血管紧张素II水平升高。提示肾内RAS激活可能通过介导饱和脂肪酸引起的内质网应激在糖尿病肾损伤中起重要作用。
Obesity-related kidney disease is related to caloric excess promoting deleterious cellular responses. Accumulation of saturated free fatty acids in tubular cells produces lipotoxicity involving significant cellular dysfunction and injury. The objectives of this study were to elucidate the role of renin-angiotensin system (RAS) activation in saturated fatty acid-induced endoplasmic reticulum (ER) stress in cultured human proximal tubule epithelial cells (HK2) and in mice fed with a high-fat diet. Treatment with saturated fatty acid palmitic acid (PA; 0.8 mM) for 24 h induced ER stress in HK2, leading to an unfolded protein response as reflected by increased expressions of the ER chaperone binding immunoglobulin protein (BiP) and proapoptotic transcription factor C/EBP homologous protein (CHOP) protein as evaluated by immunoblotting. PA treatment also induced increased protein expression of inositol requiring protein 1α (IRE1α), phosphorylated eukaryotic initiation factor-α (eIF2α), and activating transcription factor 4 (ATF4) as well as activation of caspase-3. PA treatment was associated with increased angiotensin II levels in cultured medium. The angiotensin II type 1 receptor (AT1R) blocker valsartan or renin inhibitor aliskiren dramatically suppressed PA-induced upregulation of BiP, CHOP, IRE1α, p-eIF2α, and ATF4 in HK2 cells. In contrast, valsartan or aliskiren did not prevent ER stress induced by tunicamycin. C57BL/6 mice fed with a high-fat diet for 14 wk exhibited increased protein expressions of BiP and CHOP compared with control mice, which were significantly attenuated by the valsartan treatment. Increased angiotensin II levels in serum and urine were observed in mice fed with a high-fat diet when compared with controls. It is suggested that the intrarenal RAS activation may play an important role in diabetic kidney injury via mediating ER stress induced by saturated fatty acid.