Maladaptive endoplasmic reticulum stress signaling in diabetic kidney disease (DKD) is linked to increased glomerular and tubular expression of the cell-death–promoting transcription factor C/EBP homologous protein (CHOP). Here, we determined whether locked nucleic acid (LNA)–modified antisense oligonucleotides (ASOs) targeting CHOP ameliorate experimental DKD.

We determined the efficacy of CHOP-ASO in the early and late stages of experimental DKD (in 8- or 16-week-old db/db mice, respectively) alone or with an angiotensin-converting enzyme inhibitor (ACEi), after an in vivo dose-escalation study. We used renal functional parameters and morphologic analyses to assess the effect of CHOP-ASO and renal gene-expression profiling to identify differentially regulated genes and pathways. Several human CHOP-ASOs were tested in hyperglycemia-exposed human kidney cells.

CHOP-ASOs efficiently reduced renal CHOP expression in diabetic mice and reduced markers of DKD at the early and late stages. Early combined intervention (CHOP-ASO and ACEi) efficiently prevented interstitial damage. At the later timepoint, the combined treatment reduced indices of both glomerular and tubular damage more efficiently than either intervention alone. CHOP-ASO affected a significantly larger number of genes and disease pathways, including reduced sodium-glucose transport protein 2 (Slc5a2) and PROM1 (CD133). Human CHOP-ASOs efficiently reduced glucose-induced CHOP and prevented death of human kidney cells in vitro.

The ASO-based approach efficiently reduced renal CHOP expression in a diabetic mouse model, providing an additional benefit to an ACEi, particularly at later timepoints. These studies demonstrate that ASO-based therapies efficiently reduce maladaptive CHOP expression and ameliorate experimental DKD.

糖尿病肾病 (DKD) 中的适应不良内质网应激信号与细胞死亡促进转录因子 C/EBP 同源蛋白 (CHOP) 的肾小球和肾小管表达增加有关。在这里，我们确定了靶向 CHOP 的锁定核酸 (LNA) 修饰的反义寡核苷酸 (ASO) 是否能改善实验性 DKD。

我们确定了 CHOP-ASO 在实验性 DKD 的早期和晚期（分别在 8 周或 16 周大的 db/db 小鼠中）单独或与血管紧张素转换酶抑制剂 (ACEi) 联合使用的疗效，体内剂量递增研究。我们使用肾功能参数和形态学分析来评估 CHOP-ASO 和肾基因表达谱的作用，以确定差异调节的基因和途径。在高血糖暴露的人肾细胞中测试了几种人 CHOP-ASO。

CHOP-ASOs 有效地降低了糖尿病小鼠的肾脏 CHOP 表达，并减少了早期和晚期 DKD 的标志物。早期联合干预（CHOP-ASO 和 ACEi）有效地预防了间质损伤。在稍后的时间点，联合治疗比单独干预更有效地降低了肾小球和肾小管损伤的指数。CHOP-ASO 影响了更多的基因和疾病途径，包括减少的钠-葡萄糖转运蛋白 2 (Slc5a2) 和 PROM1 (CD133)。人 CHOP-ASO 可有效降低葡萄糖诱导的 CHOP 并在体外防止人肾细胞死亡。

基于 ASO 的方法有效地降低了糖尿病小鼠模型中的肾 CHOP 表达，为 ACEi 提供了额外的好处，特别是在以后的时间点。这些研究表明，基于 ASO 的疗法可有效减少适应不良的 CHOP 表达并改善实验性 DKD。