Sirtuin 6 (Sirt6) is important for maintaining kidney homeostasis and function. Cd exposure increases the risk of developing kidney diseases. However, the role of Sirt6 in kidney disease mechanisms is unclear. Here, we evaluated the role of Sirt6 in Cd-induced kidney toxicity. After Cd exposure, p62/sequestosome-1 (SQSTM1), an autophagy substrate, accumulated in mouse kidney mesangial cells in monomeric and polyubiquitinated (polyUb) forms. Sirt6 accumulated in response to Cd treatment at concentrations below the half-maximal inhibitory concentration and decreased after 12 h of treatment. Sirt6 and p62 co-localized in the nucleus and redistributed to the cytosol after Cd treatment. Sirt6 was mainly present in nuclei-rich membrane fractions. Sirt6 interacted with p62. Ub, and microtubule-associated protein light chain 3 (LC3). Knockdown of p62 promoted Sirt6 nuclear accumulation and inhibited apoptosis. Sirt6 overexpression altered levels of polyUb-p62 and apoptosis. At earlier times during Cd treatment, polyubiquitination of p62 and apoptosis were reduced. Cytoplasmic translocation of Sirt6 occurred later, with increased polyubiquitination of p62 and apoptosis. Bafilomycin 1 (BaF1) treatment promoted cytosolic Sirt6 accumulation, increasing cell death. Silencing autophagy related 5 (Atg5) increased nuclear Sirt6 levels, reduced polyUb-p62, and inhibited cell death, indicating that autophagy was necessary for Sirt6 redistribution. Cd resistance was associated with reduced polyUb-p62 and persistent Sirt6 expression. Cd treatment in mice for 4 weeks promoted p62, Sirt6, and LC3-II accumulation, inducing apoptosis in kidney tissues. Overall, our findings show that polyUb-p62 targeted Sirt6 to autophagosomes, playing a crucial role in Cd-induced cell death and kidney damage.

Sirtuin 6 (Sirt6) 对于维持肾脏稳态和功能很重要。镉暴露会增加患肾脏疾病的风险。然而，Sirt6 在肾脏疾病机制中的作用尚不清楚。在这里，我们评估了 Sirt6 在 Cd 诱导的肾毒性中的作用。镉暴露后，p62/sequestosome-1 (SQSTM1)（一种自噬底物）以单体和多泛素化 (polyUb) 形式在小鼠肾系膜细胞中积累。 Sirt6 在低于半最大抑制浓度的浓度下响应 Cd 处理而积累，并在处理 12 小时后减少。 Sirt6 和 p62 共定位于细胞核，并在 Cd 处理后重新分布到细胞质中。 Sirt6 主要存在于富核膜组分中。 Sirt6 与 p62 相互作用。 Ub 和微管相关蛋白轻链 3 (LC3)。 p62 的敲除促进 Sirt6 核积累并抑制细胞凋亡。 Sirt6 过表达改变了聚泛素-p62 和细胞凋亡的水平。在 Cd 处理的早期，p62 的多泛素化和细胞凋亡减少。 Sirt6 的细胞质易位发生较晚，伴随着 p62 多泛素化和细胞凋亡的增加。巴弗洛霉素 1 (BaF1) 处理促进细胞质 Sirt6 积累，增加细胞死亡。沉默自噬相关 5 ( Atg5 ) 会增加核 Sirt6 水平，减少 PolyUb-p62 并抑制细胞死亡，表明自噬对于 Sirt6 重新分布是必要的。镉抗性与多聚泛素-p62 减少和持续 Sirt6 表达相关。对小鼠进行 4 周的镉治疗可促进 p62、Sirt6 和 LC3-II 的积累，从而诱导肾组织凋亡。 总的来说，我们的研究结果表明，polyUb-p62 将 Sirt6 靶向自噬体，在 Cd 诱导的细胞死亡和肾脏损伤中发挥着至关重要的作用。