Histone methyltransferase SET8 aggravates acute kidney injury through activation of p53 and downregulation of PTEN

Abstract

Abstract SET8 is a histone H4 lysine 20 methyltransferase (H4K20) that regulates transcriptional and posttranslational modifications and is related to tumorigenesis and other diseases. Its role in acute kidney injury (AKI) remains unexplored. In this study, we investigated the role and underlying mechanism of SET8 in a murine model of cisplatin-induced AKI and apoptosis of cultured murine proximal tubular epithelial cells. Following cisplatin treatment, SET8 and H4K20 mono-methylation (H4K20me1) were upregulated, coincident with reduced expression of Phosphatase and Tensin Homolog (PTEN) and increased phosphorylation of p53 both in vivo and in vitro. Administration of UNC0379, a specific inhibitor, or siRNA-mediated silencing of SET8 significantly inhibited apoptosis of TKPTs following cisplatin exposure. Similarly, UNC0379 administration in cisplatin-injected mice attenuated tubular injury, apoptosis, and improved renal function. This was concomitant with the repression of SET8, H4K20me1, and p53 phosphorylation while restoring PTEN levels. Further investigations indicated that inhibition of PTEN with Bpv or siRNA aggravated cisplatin-induced apoptosis without affecting the expression of SET8 and H4K20me1. In contrast, inhibition of p53 with Pifithrin-alpha or silencing of p53 reduced cisplatin-induced apoptosis, but these treatments did not affect the expression of SET8, H4K20me1, and PTEN. Overall, these findings suggest that inhibition of SET8 relieves apoptosis by upregulating PTEN, which in turn represses p53 phosphorylation. Additionally, inhibiting SET8 significantly suppressed the phosphorylation of the histone variant H2A and p21, two proteins associated with DNA damages in vitro and in vivo. Therefore, our results suggest that SET8 may serve as a novel therapeutic target for cisplatin-induced AKI.