Magnesium Attenuates Renal Senescence and Fibrosis With Reduced DNA Damage Response and H3K4me3 Enrichment at the p16INK4a Promoter.

Renal fibrosis is a final pathway leading to end-stage renal disease, with cellular senescence contributing to fibrosis and inflammation. Magnesium ions (Mg2+) are implicated in DNA stabilization and epigenetic regulation. In this study, we hypothesized that Mg2+ ameliorates renal fibrosis in association with reduced DNA damage responses and injury-induced cellular senescence, along with altered histone H3K4 trimethylation. To test this, we used murine models of radiation-induced organ injury and renal ischemia-reperfusion injury (IRI), along with primary cultured mouse renal proximal tubular cells. Mice received intraperitoneal MgSO4 (600 mg/kg) before radiation or IRI, with repeated dosing (300 mg/kg) after IRI. Cultured cells were treated with 6.4 mM MgSO4. We demonstrated that Mg2+ provided protection against radiation injury and reduced radiation-induced DNA damage markers in renal cells both in vitro and in vivo. Furthermore, Mg2+ suppressed IRI-induced morphological alterations, DNA damage, and cellular senescence in the kidneys, while inhibiting renal inflammation and cGAS-STING pathway activation, along with attenuation of renal fibrosis in IRI model mice. Consistent with these findings, a reduction in the expression of pro-inflammatory cytokines and fibrosis-related genes was observed. Finally, Mg2+ was associated with decreased p16INK4a transcription and reduced H3K4 trimethylation levels at its promoter in primary renal tubular cells. Our findings suggest that Mg2+ alleviates renal DNA damage while protecting against inflammation and fibrosis with accompanying epigenetic modulation. Although clinically relevant pharmacological Mg2+ dosing and therapeutic applicability require further investigation, these insights may inform therapeutic strategies targeting fibrosis and senescence-related kidney disease.