The damage of proximal tubular epithelial cells (PTECs) is considered a central event in the pathogenesis of chronic kidney disease (CKD) and deregulated repair processes of PTECs result in epithelial–mesenchymal transition (EMT), which in turn aggravates tubular injury and kidney fibrosis. In this study, we firstly revealed that the reduction of TTC36 is associated with unilateral ureteral obstruction (UUO)-induced CKD; besides, ablation of TTC36 attenuated tubular injury and subsequent EMT in UUO-treated mice kidneys. Consistently, TTC36 overexpression promoted EMT in TGF-β1-induced HK2 cells. Moreover, TTC36 elevated the protein expression of CEBPB, which was involved in the regulation of TGF-β/SMAD3 signaling, and augmented SMAD3 signaling and downstream genetic response were reduced by CEBPB silencing. Collectively, our results uncovered that TTC36 deficiency plays a protective role in tubular injury and renal fibrosis triggered by UUO; further, TTC36 overexpression exacerbated TGF-β/SMAD3 signaling via elevating the stability of SMAD3 and CEBPB, suggesting that TTC36 inhibition may be a potential strategy in the therapy of obstructive nephropathy.

近端肾小管上皮细胞 (PTECs) 的损伤被认为是慢性肾脏病 (CKD) 发病机制中的核心事件，PTECs 的失调修复过程导致上皮间质转化 (EMT)，进而加重肾小管损伤和肾纤维化. 在这项研究中，我们首先揭示了 TTC36 的减少与单侧输尿管梗阻 (UUO) 诱发的 CKD 相关；此外，在 UUO 处理的小鼠肾脏中，TTC36 的消融减轻了肾小管损伤和随后的 EMT。一致地，TTC36 过表达促进了 TGF-β1 诱导的 HK2 细胞中的 EMT。此外，TTC36 提高了 CEBPB 的蛋白质表达，CEBPB 参与了 TGF-β/SMAD3 信号传导的调节，并且 CEBPB 沉默降低了增强的 SMAD3 信号传导和下游遗传反应。集体，我们的研究结果发现，TTC36 缺乏在 UUO 引发的肾小管损伤和肾纤维化中起保护作用；此外，TTC36 过表达通过提高 SMAD3 和 CEBPB 的稳定性加剧了 TGF-β/SMAD3 信号传导，表明 TTC36 抑制可能是治疗阻塞性肾病的潜在策略。