Abstract
Diabetic nephropathy (DN) belongs to debilitating microvascular complications of diabetes and is the leading cause of end-stage renal diseases worldwide. Furthermore, outcomes from the DCCT/EDIC study showed that DN often persists and progresses despite intensive glucose control in many diabetes patients, possibly as a result of prior episode of hyperglycemia, which is called “metabolic memory.” The underlying mechanisms responsible for the development and progression of DN remain poorly understood. Activation of multiple signaling pathways and key transcription factors can lead to aberrant expression of DN-related pathologic genes in target renal cells. Increasing evidence suggests that epigenetic mechanisms in chromatin such as DNA methylation, histone acetylation, and methylation can influence the pathophysiology of DN and metabolic memory. Exciting researches from cell culture and experimental animals have shown that key histone methylation patterns and the related histone methyltransferases and histone demethylases can play important roles in the regulation of inflammatory and profibrotic genes in renal cells under diabetic conditions. Because histone methylation is dynamic and potentially reversible, it can provide a window of opportunity for the development of much-needed novel therapeutic potential for DN in the future. In this minireview, we discuss recent advances in the field of histone methylation and its roles in the pathogenesis and progression of DN.
Highlights
Diabetic nephropathy (DN) is a well-known microvascular complication of diabetes and the leading cause of end-stage renal disease (ESRD) all over the world which contributes greatly to morbidity, mortality, and most health care costs [1]
Dynamic change in H3K9me2 can be seen in both cultured monocytes (THP-1) treated with high glucose and isolated monocytes from diabetic patients with genome-wide location analyses with ChIP coupled with DNA microarrays (ChIP-on-chip) [55] and in lymphocytes from type 1 diabetic patients H3K9me2 levels linked to immune and inflammatory pathways associated with type 1 diabetes, and its complications including DN in a subset of genes are increased with ChIP-on-chip study versus healthy controls, suggesting that histone methylation is cell type specific and relatively stable regardless of age or gender [65], which open an access to understanding of the pathogenesis for the progression of DN [66]
Recent studies have shown that TGF-β stimulation in rat renal mesangial cells can increase SET7/9 gene expression and SET7/9 recruitment to the promoters of key fibrotic genes linked to DN, which are associated with active H3K4me1 occupancy; high glucose stimulation can lead to similar change in rat mesangial cell (RMC); TGF-β specific antibody treatment can reverse HG induced gene expression and promoter histone methylation changes; these results highlight a key role of histone methylation and histone methyltransferases (HMTs) SET7/9 in modulating renal gene expression leading to the pathogenesis of DN [43]
Summary
Diabetic nephropathy (DN) is a well-known microvascular complication of diabetes and the leading cause of end-stage renal disease (ESRD) all over the world which contributes greatly to morbidity, mortality, and most health care costs [1]. Despite current understanding of the mechanism of DN, still there are not enough therapeutic approaches in preventing the progression of DN to ESRD, suggesting that further mechanism and mediators should be investigated for DN Another potential reason for the long-term progression of diabetic complication in kidney could be a metabolic memory phenomenon, early exposure of the target cells to high glucose (HG), leading to persistence of its deleterious effects after effective glycemic control. We summarize this emerging area of research related to abnormal epigenetic interactions in DN, focusing on the histone lysine methylations and their roles in the development and progression of DN
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