Key Takeaways & Executive Findings
- •• P300 and H3K18ac are upregulated in diabetic nephropathy, correlating with increased KRT18 expression and necroptosis. • P300 directly regulates KRT18 transcription via H3K18 acetylation, driving RIPK1/MLKL-mediated necroptosis in tubular epithelial cells. • Inhibition of P300 with C646 or knockdown of P300/KRT18 attenuates necroptosis and may represent a therapeutic strategy for DN. • The P300-KRT18 axis is a novel epigenetic mechanism contributing to DN progression, offering potential targets for intervention.
Abstract
Diabetic nephropathy (DN) is a major cause of end-stage renal disease. While glomerular damage is a known aspect of its pathology, tubular epithelial cell necroptosis also plays a crucial role in disease progression. Epigenetic modifications, particularly histone acetylation, have garnered attention for their role in the regulation of kidney damage-related gene expression. This study explores whether the histone acetyltransferase P300 regulates KRT18 expression via histone H3 lysine 18 acetylation (H3K18ac), driving tubular epithelial cell necroptosis and accelerating DN progression. We establish an STZ-induced diabetic nephropathy mouse model and a high glucose-treated HK-2 cell model. Western blot analysis, qPCR, immunohistochemistry, and AO/PI staining are employed to assess the expression levels of P300, H3K18ac, KRT18, and necroptosis-related proteins (RIPK1 and MLKL). Functional validation of the P300-KRT18 axis is performed using shRNA interference, overexpression, and the small molecule inhibitor C646. Both in vivo and in vitro models show significant upregulation of P300, H3K18ac, and KRT18, coupled with RIPK1/MLKL pathway activation and increased cell death. P300 knockdown or C646 treatment effectively inhibits H3K18ac and KRT18 expression, reducing necroptosis; KRT18 knockdown also alleviates P300 overexpression-induced cell death. Co-transfection with P300 overexpression and KRT18 interference demonstrates that KRT18 is a key downstream effector of P300-mediated necroptosis. In conclusion, P300 upregulates KRT18 expression through H3K18 acetylation, subsequently activating the RIPK1/MLKL pathway and promoting tubular epithelial cell necroptosis. The P300-KRT18 axis may serve as a novel epigenetic therapeutic target for DN, suggesting that epigenetic regulation could be a viable intervention strategy to delay DN progression.
1. Introduction
Diabetic nephropathy (DN) is one of the most common and severe chronic complications of diabetes and has become a leading cause of end-stage renal disease (ESRD) [1,2]. Beyond glomerular damage induced by hyperglycemia, increasing evidence indicates that tubulointerstitial injury plays a crucial role in the progression of DN, with programmed cell death of tubular epithelial cells being particularly significant in the pathological process [3,4].
Necroptosis, a form of programmed cell death distinct from apoptosis, is characterized by the involvement of the RIPK1/MLKL signaling pathway, leading to cell membrane rupture and the release of inflammatory mediators [5–7]. While necroptosis has been noted in several kidney diseases, such as ischemia-reperfusion injury, IgA nephropathy, and DN [8–10], its specific upstream regulatory mechanisms, especially in relation to epigenetic modifications, remain largely unexplored.
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Qiao Zhao, Qinqin Cai, Aynigar Nizam, Qingxia Yang, Xu Liu, Fufen Meng, Zhipeng Meng (2026). P300-mediated H3K18 acetylation triggers necroptosis via modulation of KRT18 transcription in diabetic nephropathy. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2026015
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Frequently Asked Questions
What is the role of P300 in diabetic nephropathy?
P300, a histone acetyltransferase, is upregulated in diabetic nephropathy and promotes necroptosis of tubular epithelial cells by acetylating histone H3 at lysine 18 (H3K18ac), which in turn upregulates KRT18 expression and activates the RIPK1/MLKL pathway.
How does KRT18 contribute to necroptosis in diabetic nephropathy?
KRT18 is a downstream effector of P300-mediated H3K18 acetylation. Its upregulation activates the RIPK1/MLKL signaling pathway, leading to necroptosis of renal tubular epithelial cells, thereby accelerating diabetic nephropathy progression.
What is the significance of H3K18 acetylation in diabetic nephropathy?
H3K18 acetylation is an epigenetic mark that is increased in diabetic nephropathy. It is catalyzed by P300 and is associated with the transcriptional activation of KRT18, which promotes necroptosis. This highlights the role of epigenetic regulation in the pathogenesis of DN.
Can inhibiting P300 or KRT18 be a therapeutic strategy for diabetic nephropathy?
Yes, the study shows that inhibiting P300 with the small molecule C646 or knocking down KRT18 reduces necroptosis in vitro and in vivo, suggesting that targeting the P300-KRT18 axis could be a novel therapeutic approach to delay DN progression.
What experimental models were used in this study?
The study used a streptozotocin (STZ)-induced diabetic nephropathy mouse model and a high glucose-treated HK-2 human renal tubular epithelial cell model to investigate the molecular mechanisms.
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