Inhibition of Histone Methyltransferase SET8 Attenuates Renal Tubular Cell Apoptosis by Restoring PTEN in Cisplatin-Induced AKI
- AKI: Mechanisms - II
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
- Yang, Xu, Department of Medicine, Rhode Island Hospital/Alpert Medical School , Brown University, Providence, Rhode Island, United States
- Zhuang, Shougang, Brown University, Providence, Rhode Island, United States
SET8 is a histone H4K20 monomethyltransferase that regulates transcriptional and posttranslational modifications, heterochromatin formation, genomic stability, and cell cycle progression. Numerous studies have shown that SET8 is involved in various pathophysiological events, including cancer, inflammatory responses and metabolic disorders. However, its role in acute kidney injury (AKI) remains unexplored.
In this study, we aimed to investigate the role and mechanism of SET8 in cisplatin-induced AKI using a murine model and cultured renal epithelial cells.
SET8 and its downstream histone H4 lysine 20 methylation (H4K20me1) expression were highly increased in cultured murine proximal tubule epithelial (TKPT) cells and kidneys from mice treated with cisplatin, along with decreased expression of phosphatase and tensin homolog (PTEN) and increased phosphorylation of p53 (p-p53). Pharmacologic inhibition of SET8 with UNC0379, a specific inhibitor, or siRNA-mediated silencing of SET8 suppressed apoptosis, p-p53 and preserved PTEN expression in TKPT cells exposed to cisplatin. Similarly, administration of UNC0379 in cisplatin-injected mice also improved renal function, attenuated tubular injury and inhibited apoptosis, which was coincident with repressing expression of SET8, H4K20me1 and p-p53, and restoring PTEN. Moreover, inhibition of PTEN with bpv (HOpic) or silence of PTEN aggravated cisplatin-induced apoptosis without affecting expression of SET8, H4K20me1. In contrast, inhibition of p53 with pifithrin-alpha (PFA) or silence of p53 lowered cisplatin-induced apoptosis without affecting expression of SET8, H4K20me1 and PTEN.
These findings indicate that SET8 relieved renal apoptosis induced by cisplatin by upregulating PTEN, which in turn repressed p53, and suggest that SET8 may serve as a novel therapeutic target for cisplatin-induced AKI by attenuating apoptosis and restoring PTEN expression.
- NIDDK Support