SHP-1 inhibits renal ischemia reperfusion injury via dephosphorylating ASK1 and suppressing apoptosis
SHP-1 inhibits renal ischemia reperfusion injury via dephosphorylating ASK1 and suppressing apoptosis
复制标题
SHP-1通过ASK1去磷酸化和抑制细胞凋亡抑制肾缺血再灌注损伤
DOI：
10.1016/j.bbrc.2019.03.187
复制
发表时间：
2019-05-28
影响因子：
3.1
通讯作者：
Zeng，Li
中科院分区：
文献类型：
--
作者：
Tian，Hongzhe;Tan，Rumeng;Zeng，Li
肾小管上皮细胞（TECs）凋亡在肾缺血再灌注（I/R）损伤中起着至关重要的作用，但凋亡的分子调控机制仍有待进一步研究。近年来，磷酸酶家族成员被认为调控损伤和再生反应的多个方面。然而，作为一种重要的蛋白酪氨酸磷酸酶，SHP-1在肾I/R损伤调节中的作用尚不清楚。本研究发现，体内SHP-1敲低可显著增加肾I/R损伤，加重tec细胞凋亡。同样，在体外敲除tec细胞SHP-1后，发现二氯化钴诱导的细胞凋亡急剧增加。在稳定过表达SHP-1的TEC细胞系中也证实了SHP-1的保护作用。机制上，SHP-1敲除ASK1/MKK4/JNK促凋亡信号后，ASK1/MKK4/JNK促凋亡信号被过度激活，SHP-1可以结合ASK1并使其去磷酸化，抑制其活化，从而抑制细胞凋亡。
Apoptosis of tubular epithelium cells (TECs) plays critical roles in renal ischemia reperfusion (I/R) injury, but the molecular regulatory mechanisms of apoptosis still require further investigation. Recently, phosphatase family members have been suggested to regulate multiple aspects of the injury and regeneration response. However, the roles of SHP-1, an important protein-tyrosine phosphatase, in the regulation of renal I/R injury remain unknown. Here, we found that SHP-1 knockdown in vivo significantly increased renal I/R injury and aggravated the apoptosis of TECs. Consistently, after SHP-1 knockdown in TECs in vitro, a sharp increase of apoptosis induced by cobalt dichloride was found. The protective role of SHP-1 was also validated in a TEC cell line stably overexpressing SHP-1. Mechanistically, the ASK1/MKK4/JNK pro-apoptosis signal was over activated after SHP-1 knockdown, and SHP-1 could bind to and dephosphorylate ASK1 to inhibit its activation, thus repressing apoptosis.