Abstract:
HIPK2 is a multifunctional kinase that acts as a key pathogenic mediator of chronic kidney disease and fibrosis. It acts as a central effector of multiple signaling pathways implicated in kidney injury, such as TGF-β/Smad3-mediated extracellular matrix accumulation, NF-κB-mediated inflammation, and p53-mediated apoptosis. Thus, a better understanding of the specific HIPK2 regions necessary for distinct downstream pathway activation is critical for optimal drug development for CKD. Our study now shows that caspase-6-mediated removal of the C-terminal region of HIPK2 (HIPK2-CT) lead to hyperactive p65 NF-κB transcriptional response in kidney cells. In contrast, the expression of cleaved HIPK2-CT fragment could restrain the NF-κB transcriptional activity by cytoplasmic sequestration of p65 and the attenuation of IκBα degradation. Therefore, we examined whether HIPK2-CT expression can be exploited to restrain renal inflammation in vivo. The induction of HIPK2-CT overexpression in kidney tubular cells attenuated p65 nuclear translocation, expression of inflammatory cytokines, and macrophage infiltration in the kidneys of mice with unilateral ureteral obstruction and LPS-induced acute kidney injury. Collectively, our findings indicate that the HIPK2-CT is involved in the regulation of nuclear NF-κB transcriptional activity and that HIPK2-CT or its analogs could be further exploited as potential antiinflammatory agents to treat kidney disease.
摘要:
HIPK2是一种多功能激酶,可作为慢性肾脏疾病和纤维化的关键致病介质。它是与肾损伤有关的多个信号通路的主要效应物,如TGF-β/Smad3介导的细胞外基质积累,NF-κB介导的炎症,和p53介导的细胞凋亡。因此,更好地了解不同下游通路激活所必需的特定HIPK2区域对于CKD最佳药物开发至关重要.我们的研究现在表明,caspase-6介导的HIPK2C末端区域的去除(HIPK2-CT)导致肾细胞中p65NF-κB转录反应过度。相比之下,裂解的HIPK2-CT片段的表达可以通过p65的细胞质隔离和IκBα降解的减弱来抑制NF-κB的转录活性。因此,我们检查了HIPK2-CT表达是否可以在体内抑制肾脏炎症。在肾小管细胞中诱导HIPK2-CT过表达减弱p65核易位,炎性细胞因子的表达,单侧输尿管梗阻和LPS诱导的急性肾损伤小鼠肾脏巨噬细胞浸润。总的来说,我们的研究结果表明,HIPK2-CT参与核NF-κB转录活性的调节,HIPK2-CT或其类似物可进一步用作治疗肾病的潜在抗炎药.