Targeting the CDA1/CDA1BP1 Axis Retards Renal Fibrosis in Experimental Diabetic Nephropathy
Targeting the CDA1/CDA1BP1 Axis Retards Renal Fibrosis in Experimental Diabetic Nephropathy
复制标题
DOI：
10.2337/db18-0712
复制
发表时间：
2019-02-01
期刊：
影响因子：
7.7
通讯作者：
Cooper, Mark E.
中科院分区：
文献类型：
--
作者：
Chai, Zhonglin;Wu, Tieqiao;Cooper, Mark E.
靶向细胞分裂自身抗原1（CDA1）被假定可减轻糖尿病肾病中转化生长因子-β的促纤维化作用。本研究确定了一种CDA1的调节蛋白，然后利用基因和药理学方法在体内测试针对该通路的策略是否会减轻肾损伤。一种名为CDA1BP1（CDA1结合蛋白1）的新型蛋白被确定在调节CDA1的促纤维化活性中起关键作用。CDA1BP1基因缺失减轻了糖尿病小鼠肾纤维化的关键指标。此外，一系列短的合成CDA1BP1肽在体外与一种杂合肽CHA - 050竞争性抑制CDA1 - CDA1BP1结合，CHA - 050包含一个12聚体CDA1BP1肽和一种先前已知的细胞穿透肽，其剂量依赖性地降低HK - 2细胞中I型和III型胶原蛋白的表达。在体内，一种D - 氨基酸反向异构肽CHA - 061显著减轻糖尿病相关的参与纤维化和促炎通路基因在肾脏表达的增加。在一项延迟干预研究中，CHA - 061治疗逆转了糖尿病相关的肾脏内分子和病理变化。具体而言，CHA - 061显著减轻了肾细胞外基质积聚和肾小球损伤。综上所述，靶向CDA1/CDA1BP1轴是一种延缓实验性糖尿病肾病的安全、有效且可行的方法。
Targeting cell division autoantigen 1 (CDA1) is postulated to attenuate the profibrotic actions of transforming growth factor- in diabetic nephropathy. This study has identified a regulatory protein for CDA1 and has then used genetic and pharmacological approaches to test in vivo whether strategies to target this pathway would lead to reduced renal injury. A novel protein, named CDA1BP1 (CDA1 binding protein 1), was identified as critical in regulating the profibrotic activity of CDA1. Genetic deletion of CDA1BP1 attenuated key parameters of renal fibrosis in diabetic mice. Furthermore, a series of short synthetic CDA1BP1 peptides competitively inhibited CDA1-CDA1BP1 binding in vitro with a hybrid peptide, CHA-050, containing a 12mer CDA1BP1 peptide and a previously known cell-penetrating peptide, dose-dependently reducing expression of collagens I and III in HK-2 cells. In vivo, a d-amino acid retro-inverso peptide, CHA-061, significantly attenuated diabetes-associated increases in the renal expression of genes involved in fibrotic and proinflammatory pathways. In a delayed intervention study, CHA-061 treatment reversed diabetes-associated molecular and pathological changes within the kidney. Specifically, CHA-061 significantly attenuated renal extracellular matrix accumulation and glomerular injury. Taken together, targeting the CDA1/CDA1BP1 axis is a safe, efficacious, and feasible approach to retard experimental diabetic nephropathy.