凋亡信号调节激酶1(apoptosis signal-regulating kinase 1,ASK1)是丝裂原激活蛋白激酶激酶激酶(mitogen-activated protein kinase kinases kinase,MAP3K)的家族成员之一,可以响应氧化应激、内质网(endoplasmic reticulum,ER)应激等多种应激刺激,从而激活下游丝裂原激活蛋白激酶(mitogen-activated protein kinase,MAPK)中的c-Jun N末端激酶(c-Jun N-terminal kinase,JNK)和 p38 丝裂原激活蛋白激酶(p38 mitogen-activated protein kinase,p38 MAPK)信号通路,调节细胞凋亡、炎症和纤维化,介导急性肾损伤(acute kidney injury,AKI)、糖尿病肾病(diabetic kidney disease,DKD)、心肾综合征(cardio-renal syndrome,CRS)等多种肾脏疾病的进展.本文讨论了ASK1主要的激活和失活机制及其在多种肾脏疾病进展中的作用,对ASK1的抑制剂GS-4997、GS444217和GS459679进行了概述,探究ASK1抑制剂在临床应用中的潜力.
The Function of Apoptosis Signal-regulating Kinase 1 Signaling in Renal Disease
Apoptosis signal-regulating kinase 1(ASK1),a member of the mitogen-activated protein kinase kinase kinase(MAP3K)family,can respond to a variety of stress stimuli,such as oxidative stress and endoplasmic reticulum(ER)stress,thereby activating the c-Jun N-terminal kinase(JNK)and p38 mitogen-activated protein kinase(p38 MAPK)signaling pathways in downstream mitogen-activated protein kinase(MAPK)to regulate apoptosis,inflammation,and fibrosis,mediating acute kidney injury(AKI),diabetic kidney disease(DKD),cardiorenal syndrome(CRS)and other renal diseases.In this review,we discuss the major activation and inac-tivation mechanisms of ASK1,its role in the progression of multiple renal diseases.We also provide an overview of GS-4997,GS444217 and GS459679,the inhibitors of ASK1,to explore the potential of ASK1 inhibitors in clinical applications.
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