Progressive glomerulosclerosis in type 2 diabetes is associated with renal histone H3K9 and H3K23 acetylation, H3K4 dimethylation and phosphorylation at serine 10

Abstract

Background. Distinct histone modifications regulate gene expression in certain diseases but little is known about histone epigenetics in diabetic nephropathy. The current study examined the role of histone epigenetics in development and progression of nephropathy in db/db mice. Methods. We studied kidney damage in 6-month-old nondiabetic mice and type 2 diabetic db/db mice that underwent either sham surgery or uninephrectomy at 6 weeks of age which accelerates glomerulosclerosis in db/db mice via glomerular hyperfiltration. Histone H3K9 and H3K23 acetylation, H3K4 and H3K9 dimethylation and H3 phosphorylation at serine 10 was explored by western blotting of renal histone extracts. Results. Uninephrectomy in C57BL/6 mice or onset of diabetes in type 2 diabetes reduced renal H3K23 acetylation, H3K4 dimethylation and H3 phosphorylation at serine 10. In contrast, H3K9 and H3K23 acetylation, H3K4 dimethylation and H3 phosphorylation at serine 10 were significantly increased in uninephrectomized db/db mice. The disease pattern of these mice is characterized by an increased glomerular cell proliferation, severe glomerulosclerosis, albuminuria and glomerular filtration rate reduction. Treating uninephrectomized db/db mice with a Mcp-1/Ccl2 antagonist prevented the histopathological damage and the aforementioned histone modification abnormalities of advanced diabetic glomerulosclerosis. Conclusion. We conclude that advanced diabetic nephropathy is associated with increased renal H3K9 and H3K23 acetylation, H3K4 dimethylation and H3 phosphorylation at serine 10 that enhance chromatin unfolding and gene expression.

Epigenetic changes in renal genes dysregulated in mouse and rat models of type 1 diabetes

“…There are examples where the diabetic milieu has been shown to alter whole nuclear patterns of histone modifications, reflecting changes in the expression of histone-modifying enzymes. 9,41 By immunoblot analysis, we found that the protein levels of one of the two known H3K27m2/3 demethylases, KDM6A, 39 was higher in kidneys of the diabetic OVE26 mice compared with controls ( Figure 7a, left panel). In contrast, protein levels of the key H3K27 methyltransferase Ezh2 42 were not different between normal and diabetic mice (Figure 7b, left panel).…”

Valproic Acid Attenuates Proteinuria and Kidney Injury

“…Thus, we used the acetylation status of H3K9 as a measure for VPA activity in the kidney. 15,16,27 Immunohistochemistry revealed that acetyl-H3K9 is readily detected under normal conditions in the kidney cortex ( Figure 3A). Quantification showed that in all VPA-treated animals glomerular acetyl-H3K9 is increased when compared with the corresponding untreated group.…”

“…6 -9 Both inhibitors have been shown to have anti-inflammatory and antifibrotic effects in several other organs and tissues, 10,11 for example, in renal models of tubulointerstitial fibrosis and lupus. [12][13][14][15][16][17] The effect of TSA or VPA on renal cells is mainly studied in vitro. 12,13,15,18 -21 All these studies have focused on the effect of HDAC inhibitors in the renal tubulointerstitial space and their inhibition of EMT (epithelial-to-mesenchymal transition).…”

Epigenetic Diabetic Vascular Complications

“…Histone methyltransferase (HMT) SET7/9 impress regulating NF-γB expression and inflammatory gene expression through promoter H3K4 methylation in response to inflammatory diabetic stimulus (49)(50)(51). Furthermore, blood pressure control and fluid reabsorption are associated to dynamic regulation of H3K79 methylation (52)(53)(54)(55)(56). In addition, risk of diabetic complications increased as H3K4me and recruitment of SET7/9 to the insulin promoter region are augmented (38,56).…”

“…Furthermore, blood pressure control and fluid reabsorption are associated to dynamic regulation of H3K79 methylation (52)(53)(54)(55)(56). In addition, risk of diabetic complications increased as H3K4me and recruitment of SET7/9 to the insulin promoter region are augmented (38,56). Hyperglycemic memory may implicate epigenetic modifications through a transient hyperglycemia (57,58).…”