糖尿病肾病
炎症
糖尿病
癌症研究
MAPK/ERK通路
AP-1转录因子
肾病
纤维化
肾
内科学
激酶
内分泌学
肾脏疾病
生物
医学
细胞生物学
基因表达
生物化学
基因
作者
Xiaojing Yang,Wei Luo,Li Li,Xiang Hu,Mingjiang Xu,Yi Wang,Jiaxuan Feng,Jianchang Qian,Xiaofei Guan,Yunjie Zhao,Guang Liang
标识
DOI:10.1016/j.taap.2021.115465
摘要
Diabetic nephropathy (DN) is a chronic inflammatory renal disease induced by hyperglycemia. Recent studies have implicated cyclin-dependent kinase 9 (CDK9) in inflammatory responses and renal fibrosis. In this study, we explored a potential role of CDK9 in DN by using cultured mouse mesangial cell line SV40 MES-13 and streptozotocin-induced type 1 mouse model of diabetes. We inhibited CDK9 in mice and in cultured cells by a highly selective CDK9 inhibitor, LDC000067 (LDC), and evaluated inflammatory and fibrogenic outcome by mRNA and protein analyses. Our studies show that treatment of diabetic mice with LDC significantly inhibits the levels of inflammatory cytokines and fibrogenic genes in kidney specimens. These reductions were associated with improved renal function. We also found that LDC treatment suppressed MAPK-AP1 activation. We then confirmed the involvement of CDK9 in cultured SV40 MES-13 cells and showed that deficiency in CDK9 prevents glucose-induced inflammatory and fibrogenic proteins. This protection was also afforded by suppression of MAPK-AP1. Taken together, our results how that hyperglycemia activates CDK9-MAPK-AP1 axis in kidneys to induce inflammation and fibrosis, leading to renal dysfunction. Our findings also suggest that CDK9 may serve as a potential therapeutic target for DN.
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