Donner Aaron J, Yeh Steve T, Hung Gene, Graham Mark J, Crooke Rosanne M, Mullick Adam E
Antisense Drug Discovery, Isis Pharmaceuticals, Inc., Carlsbad, California, USA.
Mol Ther Nucleic Acids. 2015 Dec 1;4(12):e265. doi: 10.1038/mtna.2015.40.
Preclinical and clinical data suggest CD40 activation contributes to renal inflammation and injury. We sought to test whether upregulation of CD40 in the kidney is a causative factor of renal pathology and if reduction of renal CD40 expression, using antisense oligonucleotides (ASOs) targeting CD40, would be beneficial in mouse models of glomerular injury and unilateral ureter obstruction. Administration of a Generation 2.5 CD40 ASO reduced CD40 mRNA and protein levels 75-90% in the kidney. CD40 ASO treatment mitigated functional, transcriptional, and pathological endpoints of doxorubicin-induced nephropathy. Experiments using an activating CD40 antibody revealed CD40 is primed in kidneys following doxorubicin injury or unilateral ureter obstruction and CD40 ASO treatment blunted CD40-dependent renal inflammation. Suborgan fractionation and imaging studies demonstrated CD40 in glomeruli before and after doxorubicin administration that becomes highly enriched within interstitial and glomerular foci following CD40 activation. Such foci were also sites of ASO distribution and activity and may be predominately comprised from myeloid cells as bone marrow CD40 deficiency sharply attenuated CD40 antibody responses. These studies suggest an important role of interstitial renal and/or glomerular CD40 to augment kidney injury and inflammation and demonstrate that ASO treatment could be an effective therapy in such disorders.
临床前和临床数据表明，CD40激活会导致肾脏炎症和损伤。我们试图测试肾脏中CD40的上调是否是肾脏病理的致病因素，以及使用靶向CD40的反义寡核苷酸（ASO）降低肾脏CD40表达在肾小球损伤和单侧输尿管梗阻的小鼠模型中是否有益。给予第2.5代CD40 ASO可使肾脏中CD40 mRNA和蛋白水平降低75 - 90%。CD40 ASO治疗减轻了阿霉素诱导的肾病的功能、转录和病理终点。使用激活型CD40抗体的实验表明，在阿霉素损伤或单侧输尿管梗阻后，肾脏中的CD40被激活，而CD40 ASO治疗可减弱CD40依赖性肾脏炎症。亚器官分级分离和成像研究表明，阿霉素给药前后肾小球中的CD40在CD40激活后在间质和肾小球病灶中高度富集。这些病灶也是ASO分布和活性的部位，并且可能主要由髓样细胞组成，因为骨髓CD40缺陷会显著减弱CD40抗体反应。这些研究表明，肾间质和/或肾小球CD40在加重肾损伤和炎症方面具有重要作用，并证明ASO治疗可能是治疗此类疾病的有效方法。
