Insufficient S-sulfhydration of cAMP-response element binding protein 1 participates in hyperhomocysteinemia or cisplatin induced kidney fibrosis via promoting epithelial-mesenchymal transition.

Hydrogen sulfide (H2S) 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 H2S 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 H2S 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 H2S 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 H2S. Thus, our findings suggested that insufficient S-sulfhydration of CREB1 participated in kidney fibrosis via promoting EMT. Hence, H2S-mediated CREB1 S-sulfhydration may be an effective and potential therapeutic target for the treatment of chronic kidney disease (CKD).