Chen Shuai, Xue Ke, Zhao Rundi, Chai Jiayin, Zhu Xinyu, Kong Xiangning, Ding Yuqing, Xu Lijia, Wang Wen
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
Department of Pathology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
Free Radic Biol Med. 2025 Sep;237:312-325. doi: 10.1016/j.freeradbiomed.2025.05.436. Epub 2025 Jun 3.
Hydrogen sulfide (HS) has been reported to alleviate kidney injury in chronic kidney disease (CKD). Epithelial-mesenchymal transition (EMT) is the essential mechanism of kidney fibrosis. However, the underlying mechanism needs to be further explored. In the present study, we found that both serum and renal HS level were down-regulated in hyperhomocysteinemia (HHcy) or cisplatin induced kidney dysfunction. cAMP-response element binding protein 1 (CREB1) is a crucial transcription factor involved in the development of fibrosis in multiple organs. The NaHS (exogenous HS donor)-mediated S-sulfhydration of CREB1 inhibited the nuclear translocation of itself and the consequent gene expression of inflammation and fibrosis factors. Located in nuclear localization sequence, Cys286 was the effective S-sulfhydration site of CREB1. We showed that the protection conferred by HS was blocked by the mutation of CREB1 Cys286. Consistently, the transcriptional activity of CREB1 and EMT suppressed were reversed. Administration of NaHS alleviated kidney injury through epithelial-mesenchymal transition (EMT). Zinc finger E-box binding homeobox 1 (ZEB1) is an essential and direct transcription factor in EMT. Mechanistically, binding of CREB1 and ZEB1 was prevented by HS. Thus, our findings suggested that insufficient S-sulfhydration of CREB1 participated in kidney fibrosis via promoting EMT. Hence, HS-mediated CREB1 S-sulfhydration may be an effective and potential therapeutic target for the treatment of chronic kidney disease (CKD).
据报道，硫化氢（HS）可减轻慢性肾脏病（CKD）中的肾损伤。上皮-间质转化（EMT）是肾纤维化的关键机制。然而，其潜在机制仍需进一步探索。在本研究中，我们发现高同型半胱氨酸血症（HHcy）或顺铂诱导的肾功能障碍中，血清和肾脏HS水平均下调。环磷酸腺苷反应元件结合蛋白1（CREB1）是一种关键的转录因子，参与多个器官纤维化的发展。NaHS（外源性HS供体）介导的CREB1的S-硫氢化抑制了其自身的核转位以及随后炎症和纤维化因子的基因表达。位于核定位序列中的Cys286是CREB1的有效S-硫氢化位点。我们发现，CREB1 Cys286的突变阻断了HS赋予的保护作用。一致地，CREB1的转录活性和EMT抑制作用被逆转。给予NaHS通过上皮-间质转化（EMT）减轻了肾损伤。锌指E盒结合同源框1（ZEB1）是EMT中一种重要且直接的转录因子。机制上，HS阻止了CREB1与ZEB1的结合。因此，我们的研究结果表明，CREB1的S-硫氢化不足通过促进EMT参与了肾纤维化。因此，HS介导的CREB1 S-硫氢化可能是治疗慢性肾脏病（CKD）的一种有效且潜在的治疗靶点。
