The development of diabetic nephropathy (DN) could be promoted by the occurrence of tubulointerstitial fibrosis (TIF), which has a close relationship with mitochondrial dysfunction of renal tubular epithelial cells (RTECs). As a key regulator of metabolic homeostasis, Yin Yang 1 (YY1) plays an important role not only in regulating the fibrosis process but also in maintaining the mitochondrial function of pancreatic β-cells. However, it was not clear whether YY1 participated in maintaining mitochondrial function of RTECs in early DN-associated TIF. In this study, we dynamically detected mitochondrial functions and protein expression of YY1 in db/db mice and high glucose (HG)-cultured HK-2 cells. Our results showed that comparing with the occurrence of TIF, the emergence of mitochondrial dysfunction of RTECs was an earlier even, besides the up-regulated and nuclear translocated YY1. Correlation analysis showed YY1 expressions were negatively associated with PGC-1α in vitro and in vivo. Further mechanism research demonstrated the formation of mTOR-YY1 heterodimer induced by HG up-regulated YY1, the nuclear translocation of which inactivated PGC-1α by binding to the PGC-1α promoter. Overexpression of YY1 induced mitochondrial dysfunctions in normal glucose-cultured HK-2 cells and 8-weeks-old db/m mice. While, dysfunctional mitochondria induced by HG could be improved by knockdown of YY1. Finally, downregulation of YY1 could retard the progression of TIF by preventing mitochondrial functions, resulting in the improvement of epithelial-mesenchymal transition (EMT) in early DN. These findings suggested that YY1 was a novel regulator of mitochondrial function of RTECs and contributed to the occurrence of early DN-associated TIF.

肾小管间质纤维化（TIF）的发生可促进糖尿病肾病（DN）的发生发展，TIF与肾小管上皮细胞（RTECs）线粒体功能障碍密切相关。作为代谢稳态的关键调节因子，阴阳 1 (YY1) 不仅在调节纤维化过程中发挥重要作用，而且在维持胰腺 β 细胞的线粒体功能方面也发挥着重要作用。然而，尚不清楚 YY1 是否参与维持早期 DN 相关 TIF 中 RTEC 的线粒体功能。在本研究中，我们动态检测了db/db中 YY1 的线粒体功能和蛋白表达小鼠和高糖 (HG) 培养的 HK-2 细胞。我们的结果表明，与 TIF 的发生相比，除了上调和核转位的 YY1 外，RTECs 线粒体功能障碍的出现甚至更早。相关性分析表明，YY1表达在体外和体内均与PGC-1α呈负相关。进一步的机制研究表明，HG 诱导的 mTOR-YY1 异二聚体的形成上调 YY1，其核转位通过与 PGC-1α 启动子结合而使 PGC-1α 失活。YY1 过表达诱导正常葡萄糖培养的 HK-2 细胞和 8 周龄db/m线粒体功能障碍老鼠。同时，HG 诱导的功能失调的线粒体可以通过敲低 YY1 得到改善。最后，下调 YY1 可通过阻止线粒体功能来延缓 TIF 的进展，从而改善早期 DN 的上皮-间质转化 (EMT)。这些发现表明 YY1 是 RTEC 线粒体功能的新型调节剂，并有助于早期 DN 相关 TIF 的发生。