Deletion of SETD7 attenuates systemic inflammation triggered by renal ischemia–reperfusion injury

The sudden loss of kidney function within hours to 7 days is called acute kidney injury (AKI), which is mainly caused by ischemia and reperfusion and involves multiple mechanisms, including epigenetic alterations. SETD7 plays a regulatory role in gene expression by methylating histone and non-histone proteins and has been implicated in inflammatory pathways and diabetic nephropathy. However, its deep implications in AKI are still lacking. In this study, we investigated the role of SETD7 in an experimental model of AKI induced by renal ischemia–reperfusion (I/R). Male C57BL/6 wild-type (WT) and global SETD7 knockout (KO) mice were subjected to unilateral renal ischemia followed by 15 days of reperfusion. To assess the model's success, renal function, injury and fibrosis markers, and morphometric parameters were assessed. Next, SETD7 localization and histone methylation were evaluated. The influence of SETD7 knockout on local and systemic inflammatory cytokines was analyzed. Renal ischemia markedly increased the expression of injury and fibrosis markers in the affected kidney by more than 20-fold compared with WT controls: KIM-1, NGAL, vimentin, COL3 and α-SMA ( p < 0.05). SETD7 was found in the cytoplasm. The SETD7 knockout animals presented an attenuated systemic inflammatory response (less than 9-fold compared to WT control, p < 0.05), but not a local. Collectively, these findings indicate that SETD7 plays a significant role in modulating systemic inflammation following renal ischemic injury; inhibiting SETD7 expression and function could be a novel therapeutic strategy to control AKI inflammatory stimuli.