The accumulation of advanced glycation end products (AGEs) is a hallmark of prolonged high glucose levels in diabetes mellitus. We have previously reported that hypoxia and AGEs cause epigenetic modification of the repressive mark H3K27me3 in podocytes by downregulation of enhancer of zeste homolog 2 (EZH2) and nuclear inhibitor of protein phosphatase 1 (NIPP1). However, their impact on proximal tubular cells remains unclear. The aim of this study was to investigate the role of AGEs and diabetes on the epigenetic modifications of EZH2 and H3K27me3 in proximal tubular cells and in diabetic (db/db) mice. Our results show that AGEs reduced EZH2 expression in TKPTS cells, thereby decreasing the tri-methylation of H3K27. qRT-PCR analysis revealed upregulation of genes known to contribute to diabetic nephropathy and kidney injury as Ctgf, Snai1, and p27^Kip1. Consistently, immunofluorescent staining of renal sections from db/db mice confirmed the reduction in H3K27me3 levels in proximal tubules compared to non-diabetic controls. In summary, we show that AGEs induce epigenetic changes in proximal tubular cells by suppressing EZH2, thereby facilitating the transcription of genes involved in progression of diabetic nephropathy. These results provide new insights into metabolic memory, a process in which prior poor glucose control triggers ongoing renal damage despite current normoglycemia.

Type 2 diabetes mellitus (T2DM) is a major age-associated metabolic disease, and aging substantially contributes to the increasing burden and progression of chronic complications, including diabetic kidney disease (DKD). However, the molecular mechanisms underlying changes in renal susceptibility during disease progression remain incompletely understood. We hypothesized that the scaffold protein mitogen-activated protein kinase organizer 1 (MORG1/WDR83) contributes to stage-dependent differences in DKD and that these effects may vary according to biological sex. Heterozygous Morg1 deletion was introduced into the diabetic C57BLKS/J db/db mouse model, and male and female mice were analysed at early and later disease stages alongside non-diabetic controls. Renal fibrosis, albuminuria, HIF-1α expression, mTORC1 and ERK1/2 activity, and renal cortical gene expression were assessed. Morg1 haploinsufficiency was associated with reduced renal fibrosis and albuminuria during early diabetes, whereas these protective effects were less evident in later-stage diabetic animals. HIF-1α expression decreased during progression in most groups but was relatively preserved in later-stage female Morg1 heterozygotes, whereas mTORC1 and ERK1/2 signalling was altered in a genotype- and stage-dependent manner. These findings identify MORG1 as a context-dependent modifier of DKD whose renoprotective effects change across disease progression, linking MORG1-associated signalling to the evolving renal phenotype of an age-associated metabolic disease.