Inhibition of c-Src/p38 MAPK pathway ameliorates renal tubular epithelial cells apoptosis in db/db mice
Inhibition of c-Src/p38 MAPK pathway ameliorates renal tubular epithelial cells apoptosis in db/db mice
复制标题
抑制 c-Src/p38 MAPK 通路可改善 db/db 小鼠肾小管上皮细胞凋亡
DOI：
10.1016/j.mce.2015.09.008
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发表时间：
2015-12-05
影响因子：
4.1
通讯作者：
Duan, Huijun
中科院分区：
文献类型：
--
作者：
Wu, Haijiang;Shi, Yonghong;Duan, Huijun
肾小管上皮细胞（Renal tubular epithelial cells，RTEC）凋亡在糖尿病肾病（diabetic nephropathy，DN）的发生、发展中起着重要作用，被认为是高血糖导致肾功能衰竭的重要原因之一，但其确切机制尚不清楚。在本研究中，我们研究了c-Src/p38 MAPK通路的抑制如何影响RTEC凋亡。对糖尿病db/db小鼠每隔一天腹膜内给予c-Src抑制剂PP 2，持续8周，显著降低其肾脏重量、每日尿量、血糖、血尿素氮、血清肌酐、甘油三酯和尿白蛋白排泄，同时还观察到c-Src和p38 MAPK的失活，沿着肾脏中Bax/Bcl-2比率和切割的caspase-3水平的降低。在体外，HK-2细胞（人RTEC系）暴露于高糖（HG）促进c-Src和p38 MAPK的磷酸化，随后，如蛋白质印迹法、TUNEL测定法和流式细胞术所示，增加细胞死亡，这可以被PP 2抑制。特别是，一个特定的p38 MAPK抑制剂，SB 203580，既衰减HG诱导的c-Src激活和废除的表达的PPAR γ和CHOP，也减少凋亡。总之，PP 2抑制c-Src，因此减少RTEC中的细胞凋亡，这至少部分是由于糖尿病肾脏中抑制的p38 MAPK活化。(C)2015爱思唯尔爱尔兰有限公司版权所有。
Renal tubular epithelial cells (RTEC) apoptosis, which plays a key role in the pathogenesis and progression of diabetic nephropathy (DN), is believed to be contributive to the hyperglycemia-induced kidney failure, though the exact mechanisms remain elusive. In this study, we investigated how inhibition of c-Src/p38 MAPK pathway would affect RTEC apoptosis. The c-Src inhibitor PP2 i.p. administered every other day for 8 weeks to diabetic db/db mice significantly reduced their kidney weights, daily urinary volumes, blood glucose, blood urea nitrogen, serum creatinine, triglyceride and urine albumin excretion, whereas deactivation of c-Src and p38 MAPK were also observed, along with decreases in both Bax/Bcl-2 ratio and cleaved caspase-3 level in the kidneys. In vitro, exposure of HK-2 cells (a human RTEC line), to high glucose (HG) promoted phosphorylation of c-Src and p38 MAPK, and subsequently, as revealed by western blotting, TUNEL assay and flow cytometry, increased cell death, which can be inhibited by PP2. Especially, a specific p38 MAPK inhibitor, SB203580, that both attenuated HG-induced c-Src activation and abrogated the expression of PPAR gamma and CHOP, also reduced apoptosis. Taken together, PP2 inhibits c-Src and therefore reduces apoptosis in RTEC, which at least in part, is due to suppressed p38 MAPK activation in diabetic kidney. (C) 2015 Elsevier Ireland Ltd. All rights reserved.