Targeting MLL1/WDR5‐Mediated Epigenetic Regulation Mitigates Peritoneal Fibrosis by Reducing p16INK4a DOI Creative Commons
Daisuke Hara, Kensuke Sasaki, Shigehiro Doi

et al.

The FASEB Journal, Journal Year: 2025, Volume and Issue: 39(8)

Published: April 15, 2025

ABSTRACT Peritoneal fibrosis poses a significant challenge to the long‐term efficacy of peritoneal dialysis (PD), with emerging evidence highlighting role cellular senescence in its pathogenesis. p16 INK4a is cell cycle regulator that has been implicated senescence. Mixed‐lineage leukemia 1 (MLL1) forms complex WD‐40 repeat protein 5 (WDR5) and exhibits histone H3K4 methyltransferase activity. We have previously shown inhibition MLL1/WDR5 reduces expression attenuates renal after injury mice. This study aimed investigate whether inhibiting senescence, inflammation, both human samples mice methylglyoxal (MGO)‐induced (MGO‐injected mice), while also exploring associated underlying mechanisms. MLL1/WDR5, 3 lysine 4 trimethylation (H3K4me3), were elevated TGF‐β1‐stimulated mesothelial cells (HPMCs), non‐adherent obtained from patients undergoing PD, submesothelial compact zones MGO‐injected Notably, these was positively correlated dialysate/plasma creatinine ratio. Treatment protein–protein interaction inhibitors MM‐102 OICR‐9429 reduced H3K4me3 levels expression, suppressing HPMCs as well inflammation These improved function Additionally, we demonstrated MLL1/WDR5‐induced directly regulates gene transcription, H3K4me3, thereby transcription. findings suggest targeting activation alleviates fibrosis, potential promising therapeutic strategy for fibrosis.

Language: Английский

Targeting MLL1/WDR5‐Mediated Epigenetic Regulation Mitigates Peritoneal Fibrosis by Reducing p16INK4a DOI Creative Commons
Daisuke Hara, Kensuke Sasaki, Shigehiro Doi

et al.

The FASEB Journal, Journal Year: 2025, Volume and Issue: 39(8)

Published: April 15, 2025

ABSTRACT Peritoneal fibrosis poses a significant challenge to the long‐term efficacy of peritoneal dialysis (PD), with emerging evidence highlighting role cellular senescence in its pathogenesis. p16 INK4a is cell cycle regulator that has been implicated senescence. Mixed‐lineage leukemia 1 (MLL1) forms complex WD‐40 repeat protein 5 (WDR5) and exhibits histone H3K4 methyltransferase activity. We have previously shown inhibition MLL1/WDR5 reduces expression attenuates renal after injury mice. This study aimed investigate whether inhibiting senescence, inflammation, both human samples mice methylglyoxal (MGO)‐induced (MGO‐injected mice), while also exploring associated underlying mechanisms. MLL1/WDR5, 3 lysine 4 trimethylation (H3K4me3), were elevated TGF‐β1‐stimulated mesothelial cells (HPMCs), non‐adherent obtained from patients undergoing PD, submesothelial compact zones MGO‐injected Notably, these was positively correlated dialysate/plasma creatinine ratio. Treatment protein–protein interaction inhibitors MM‐102 OICR‐9429 reduced H3K4me3 levels expression, suppressing HPMCs as well inflammation These improved function Additionally, we demonstrated MLL1/WDR5‐induced directly regulates gene transcription, H3K4me3, thereby transcription. findings suggest targeting activation alleviates fibrosis, potential promising therapeutic strategy for fibrosis.

Language: Английский

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