Huynh Pacific, Yang Yuxin, Tian Hua, Wu Tieqiao, Huang Minling, Tang Jiali, Dai Aozhi, Cooper Mark E, Chai Zhonglin
Department of Diabetes, School of Translational Medicine, Monash University, Melbourne, VIC 3004, Australia.
Int J Mol Sci. 2025 Feb 26;26(5):2022. doi: 10.3390/ijms26052022.
Cell Division Autoantigen 1 (CDA1) has been shown to play a role in enhancing transforming growth factor beta (TGFβ) signaling, leading to fibrosis in diabetic kidney disease (DKD) using mouse strains with global CDA1 gene deletion. In these models, diabetes has been induced, leading to DKD in the absence of CDA1. It is still unknown whether inhibition of CDA1 activity after onset of diabetes in the presence of CDA1 can attenuate renal fibrosis in vivo. Thus, we examined the effect of inducing genetic deletion of CDA1 in adulthood in mice using a tamoxifen-activated estrogen receptor fused cyclization recombinase (ERCre)-Locus of cross-over in P1 (LoxP) system. Male mice at 6-8 weeks of age were rendered diabetic with streptozotocin (STZ) or injected with buffer alone to serve as non-diabetic controls. Five weeks later, genetic deletion of CDA1 was induced by tamoxifen administration in CDA1Flox/ERCre mice, with mice injected with vehicle to serve as CDA1 wildtype controls. Kidney tissues were analyzed 5 weeks after deletion of CDA1. Tamoxifen administration reduced CDA1 gene expression by ~80% in CDA1Flox/ERCre mice. Renal levels of phosphorylated Smad3 and expression of profibrotic genes as well as accumulation of extracellular matrix proteins (ECMs) such as collagens III and IV were increased in diabetic mice, and induced deletion of CDA1 led to attenuation of these parameters. Therefore, targeting CDA1 after onset of diabetes in mice where CDA1 was initially expressed is able to attenuate diabetes-associated renal injury, providing the impetus to target this pathway in order to reduce diabetic kidney disease.
细胞分裂自身抗原1（CDA1）已被证明在增强转化生长因子β（TGFβ）信号传导中发挥作用，在使用全球CDA1基因缺失的小鼠品系中导致糖尿病肾病（DKD）的纤维化。在这些模型中，已诱发糖尿病，导致在没有CDA1的情况下发生DKD。糖尿病发病后，在存在CDA1的情况下抑制CDA1活性是否能在体内减轻肾纤维化仍是未知的。因此，我们使用他莫昔芬激活的雌激素受体融合环化重组酶（ERCre）-P1交叉位点（LoxP）系统，研究了成年小鼠中诱导CDA1基因缺失的效果。6-8周龄的雄性小鼠用链脲佐菌素（STZ）诱导糖尿病，或仅注射缓冲液作为非糖尿病对照。五周后，在CDA1Flox/ERCre小鼠中通过给予他莫昔芬诱导CDA1基因缺失，注射载体的小鼠作为CDA1野生型对照。在CDA1缺失5周后分析肾脏组织。给予他莫昔芬使CDA1Flox/ERCre小鼠中的CDA1基因表达降低约80%。糖尿病小鼠中磷酸化Smad3的肾脏水平、促纤维化基因的表达以及细胞外基质蛋白（ECM）如III型和IV型胶原的积累增加，诱导CDA1缺失导致这些参数的减弱。因此，在最初表达CDA1的小鼠中糖尿病发病后靶向CDA1能够减轻糖尿病相关的肾损伤，为靶向该途径以减少糖尿病肾病提供了动力。
