ASK1 contributes to fibrosis and dysfunction in mode of kidney disease
ASK1 contributes to fibrosis and dysfunction in mode of kidney disease
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DOI：
10.1172/jci99768
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发表时间：
2018-10-01
影响因子：
15.9
通讯作者：
Breckenridge, David G.
中科院分区：
文献类型：
--
作者：
Liles, John T.;Corkey, Britton K.;Breckenridge, David G.
氧化应激是急性和慢性肾脏疾病的潜在组成部分。凋亡信号调节激酶1（ASK 1）是一种广泛表达的氧化还原敏感性丝氨酸苏氨酸激酶，可激活p38和c-Jun N-末端激酶（JNK）丝裂原活化蛋白激酶激酶，并在氧化应激环境中诱导凋亡、炎症和纤维化信号。我们描述了一种有效的选择性小分子ASK 1抑制剂GS-444217的发现和表征，并证明了ASK 1抑制剂在减少肾损伤和纤维化方面的治疗潜力。在糖尿病肾病（DKD）患者的肾活检中证实了肾小球和肾小管隔室中ASK 1通路的激活，并且在几种代表DU病理学特征的肾损伤和纤维化啮齿动物模型中，GS-444217降低了该激活。GS-444217治疗减少了肾脏中的进行性炎症和纤维化，并阻止了肾小球滤过率下降。GS-444217与依那普利（一种血管紧张素转换酶抑制剂）联合使用，可使蛋白尿减少更多，肾小球硬化消退。这些结果将ASK 1确定为肾脏疾病的重要靶点，并支持ASK 1抑制剂治疗DIM的临床开发。
Oxidative stress is an underlying component of acute and chronic kidney disease. Apoptosis signal-regulating kinase 1 (ASK1) is a widely expressed redox-sensitive serine threonine kinase that activates p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase kinases, and induces apoptotic, inflammatory, and fibrotic signaling in settings of oxidative stress. We describe the discovery and characterization of a potent and selective small-molecule inhibitor of ASK1, GS-444217, and demonstrate the therapeutic potential of ASK1 inhibition to reduce kidney injury and fibrosis. Activation of the ASK1 pathway in glomerular and tubular compartments was confirmed in renal biopsies from patients with diabetic kidney disease (DKD) and was decreased by GS-444217 in several rodent models of kidney injury and fibrosis that collectively represented the hallmarks of DU pathology. Treatment with GS-444217 reduced progressive inflammation and fibrosis in the kidney and halted glomerular filtration rate decline. Combination of GS-444217 with enalapril, an angiotensin-converting enzyme inhibitor, led to a greater reduction in proteinuria and regression of glomerulosclerosis. These results identify ASK1 as an important target for renal disease and support the clinical development of an ASK1 inhibitor for the treatment of DIM.