Tetratricopeptide repeat domain 36 deficiency mitigates renal tubular injury by inhibiting TGF-β1-induced epithelial–mesenchymal transition in a mouse model of chronic kidney disease

• Published in: Genes & diseases 2022-11, Vol.9 (6), p.1716-1726
• Main Authors: Yan, Xin, Peng, Rui, Ni, Yilu, Chen, Lei, He, Qingling, Li, Qianyin, Zhou, Qin
• Format: Article
• Language: English
• Subjects: CCAAT enhancer binding protein beta; Chronic kidney disease; Epithelial−mesenchymal transition; Full Length; Renal fibrosis; SMAD family bember 3; Tetratricopeptide repeat domain 36
• ISSN: 2352-3042; 2352-4820; 2352-3042
• DOI: 10.1016/j.gendis.2021.04.005

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.