Magnesium Attenuates Renal Senescence and Fibrosis With Reduced DNA Damage Response and H3K4me3 Enrichment at the p16^INK4a Promoter.

Authors

Makoto Matsubara, Kensuke Sasaki, Shigehiro Doi, Takeshi Ike, Maria Yoshida, Akira Takahashi, Yosuke Osaki, Naoki Ishiuchi, Aiko Okubo, Yujiro Maeoka, Takuto Chiba, Ayumu Nakashima, Takao Masaki

Published in

FASEB journal : official publication of the Federation of American Societies for Experimental Biology. Volume 40. Issue 16. Pages e72192. Aug 31, 2026.

Abstract

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 p16^INK4a 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.

PMID:
42600046
Bibliographic data and abstract were imported from PubMed on 15 Aug 2026.

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