SIRT2 inhibition attenuates myofibroblast transition through autophagy-mediated ciliogenesis in renal epithelial cells.

Myofibroblast transition plays a crucial role in both fibrotic diseases and wound healing. Although SIRT2 regulates fibrosis, its mechanisms of action remain poorly understood. This study aimed to investigate the effects of SIRT2 inhibition on myofibroblast transition in human renal cells under quiescent conditions. HK-2 kidney proximal tubular epithelial cells were starved of serum, resulting in the formation of primary cilia. Transforming growth factor-β (TGF-β) stimulation reduced both the number of ciliated cells and ciliary length. The ciliary defects resulted from a failure in autophagy termination, leading to the accumulation of OFD1, a negative regulator of ciliogenesis, at centriolar satellites. This phenomenon was correlated with the upregulation of fibrosis-related proteins. To elucidate the role of SIRT2 in the autophagy-ciliogenesis-fibrosis axis, cells were treated with AGK2, a specific inhibitor of SIRT2. AGK2 treatment promoted the formation of both autophagosomes and autolysosomes and facilitated OFD1 degradation at the centriolar satellites, resulting in the lengthening of primary cilia. Restoration of primary cilia by AGK2 was associated with the suppression of myofibroblast transition. In conclusion, SIRT2 inhibition attenuates TGF-β-induced fibrosis by promoting autophagy-mediated ciliogenesis. This study highlights SIRT2 as a potential therapeutic target for fibrotic diseases.