Tetratricopeptide repeat domain 36 deficiency mitigates renal tubular injury by inhibiting TGF-b1-induced epithelial-mesenchymal transition in a mouse model of chronic kidney disease

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 asso-ciated 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-I31-induced HK2 cells. Moreover, TTC36 elevated the protein expression of CEBPB, which was involved in the regulation of TGF-I3/SMAD3 signaling, and augmented SMAD3 signaling and downstream genetic response were reduced by CEBPB silencing. Collectively, our results uncovered that TTC36 deficiency plays a protec-tive role in tubular injury and renal fibrosis triggered by UUO; further, TTC36 overexpression exacerbated TGF-I3/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. Copyright (c) 2021, Chongqing Medical University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).

Automated summary

This study revealed the association between TTC36 reduction and CKD induced by unilateral ureteral obstruction (UUO), and showed that ablation of TTC36 attenuated tubular injury and subsequent EMT. TTC36 overexpression promoted EMT in TGF-I31-induced HK2 cells. Moreover, TTC36 elevated the protein expression of CEBPB, which regulated TGF-I3/SMAD3 signaling.