SMYD3 as an Epigenetic Regulator of Renal Tubular Cell Survival and Regeneration Following Acute Kidney Injury in Mice.

The protein SET and MYND-Domain Containing 3 (SMYD3) is a methyltransferase that modifies various non-histone and histone proteins, linking it to tumorigenesis and cyst formation. However, its role in acute kidney injury (AKI) remains unclear. This study investigates the role and mechanism of AKI using a murine model of ischemia-reperfusion (IR)-induced AKI. After IR injury, SMYD3 and H3K4me3 levels increased in the kidneys, correlating with renal dysfunction, tubular cell injury, and apoptosis. Administration of BCI-121, a selective SMYD3 inhibitor, exacerbated IR-induced tubular cell injury and apoptosis, leading to more severe renal dysfunction and pathological changes. Pharmacological inhibition of SMYD3 also impaired the dedifferentiation and proliferation of renal tubular cells, key regenerative processes in injured kidneys, as evidenced by decreased expression of vimentin, snail, proliferating cell nuclear antigen (PCNA), cyclin D1, and retinoblastoma protein (RB). Additionally, SMYD3 inhibition reduced phosphorylation of the epithelial growth factor receptor (EGFR) and AKT, as well as EGFR expression in damaged kidneys. Finally, both BCI-121 and SMYD3 siRNA reduced EGF-induced expression of vimentin, snail, cyclin D1, PCNA, and EGFR, along with phosphorylation of RB and AKT in cultured renal tubular cells. Chip assay indicated that SMYD3 and H3K4me3 are enriched at the promoter of EGFR and SMYD3 inhibition blocked this response. These data suggest that SMYD3 plays an important role as an epigenetic regulator of renal tubular cell survival and regenerative pathways following kidney injury. Targeting SMYD3 or its epigenetic effects could offer therapeutic potential for enhancing kidney regeneration in AKI and related renal diseases.