TSC1 deletion in fibroblasts alleviates lipopolysaccharide-induced acute kidney injury
TSC1 deletion in fibroblasts alleviates lipopolysaccharide-induced acute kidney injury
复制标题
成纤维细胞中 TSC1 缺失可减轻脂多糖诱导的急性肾损伤。
DOI：
10.1042/cs20180348
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发表时间：
2018-10-15
期刊：
影响因子：
6
通讯作者：
Bai, Xiaochun
中科院分区：
文献类型：
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作者：
Shen, Junhui;Cui, Zhong-Kai;Bai, Xiaochun
雷帕霉素复合体1的机制靶点(MTORC1)信号在炎症反应中是活跃的，但其在感染性急性肾损伤(AKI)中的作用尚未被证明。在1.5 mg/kg脂多糖(LPS)诱导的小鼠AKI模型中，肾成纤维细胞的mTORC1活化(p-S6)增加。在成纤维细胞(fio-TSC1-/-)中缺失mTORC1负性调节因子结节性硬化症复合体1(TSC1-/-)，与TSC1fl/fl对照小鼠相比，AKI小鼠血清肌酐和血尿素氮水平的升高均受到抑制。内皮素-1(EDN1)和磷酸化-JUN-氨基末端激酶(p-JNK)在内毒素诱导的肾成纤维细胞中表达上调。在注射脂多糖后，mTORC1抑制剂雷帕霉素和EDN1拮抗剂波生坦可消除TSC1f1/f1和fio-TSC1-/-小鼠肾功能的差异。雷帕霉素能恢复内毒素诱导的TSC1基因敲除小鼠胚胎成纤维细胞(MEF)中EDN1、ECE1和p-JNK的上调。Jun氨基末端激酶(JNK)抑制剂SP600125可减弱内毒素对TSC1基因敲除MEF中EDN1和ECE1的增强作用，但不改变p-S6核糖体蛋白(p-S6)水平。结果表明，依赖mTORC1JNK上调的ECE1基因上调了TSC1基因敲除小鼠肾成纤维细胞的EDN1，有助于改善脂多糖诱导的AKI小鼠的肾功能。肾成纤维细胞mTORC1在感染性AKI中起重要作用。
Mechanistic target of rapamycin complex 1 (mTORC1) signaling is active in inflammation, but its involvement in septic acute kidney injury (AKI) has not been shown. mTORC1 activation (p-S6) in renal fibroblasts was increased in a mouse AKI model induced by 1.5 mg/kg lipopolysaccharide (LPS). Deletion of tuberous sclerosis complex 1 (TSC1), an mTORC1 negative regulator, in fibroblasts (Fibro-TSC1-/-) inhibited the elevation of serum creatinine and blood urea nitrogen in AKI compared with that in TSC1fl/fl control mice. Endothelin-1 (EDN1) and phospho-Jun-amino-terminal kinase (p-JNK) were up-regulated in Fibro-TSC1-/- renal fibroblasts after LPS challenge. Rapamycin, an mTORC1 inhibitor, and bosentan, an EDN1 antagonist, eliminated the difference in renal function between TSC1fl/fl and Fibro-TSC1-/- mice after LPS injection. Rapamycin restored LPS-induced up-regulation of EDN1, endothelin converting enzyme-1 (ECE1), and p-JNK in TSC1-knockdown mouse embryonic fibroblasts (MEFs). SP600125, a Jun-amino-terminal kinase (JNK) inhibitor, attenuated LPS-induced enhancement of EDN1 and ECE1 in TSC1-knockdown MEFs without a change in phospho-S6 ribosomal protein (p-S6) level. The results indicate that mTORC1-JNK-dependent up-regulation of ECE1 elevated EDN1 in TSC1-knockout renal fibroblasts and contributed to improvement of renal function in Fibro-TSC1-/- mice with LPS-induced AKI. Renal fibroblast mTORC1 plays an important role in septic AKI.