The Role Of Histone Modifications in The Pathogenesis Of Diabetic Kidney Disease Ⅱ

7. Histone Acetylation and Apoptosis in DKD 

Blockade of HDAC4 signaling increased the H3K9Ac levels in the miR-29a proximal promoter and miR-29a transcription in hyperglycemia-treated podocytes and attenuated the hyperglycemia-induced apoptosis [34]. In another study, the acetylation of histone H4 in the glucose-regulated protein (GRP78) promoter, was increased in the DKD group, compared with controls; valproate reversed apoptosis by increasing the acetylation of histone H4 in the GRP78 promoter and decreasing the acetylation of histone H4 in the C/EBP-homologous protein (CHOP) promoter, two promoters that encode proteins related to ER stress [81]. 

8. Histone Acetylation and Other Manifestations of DKD

Hyperglycemia-induced Txnip expression was associated with the enrichment of H3K9ac at the promoter region of the gene in the kidneys of diabetic mice [82]. ChIP assays showed increased levels of H3K18Ac and H2BK5Ac in the membrane metallocene endopeptidase (Mme) promoter region in the kidneys of diabetic rats but enrichment of H2AK5Ac remained unchanged on Mme promoter in kidneys [83]. The expression of ULK1 in diabetic mice was decreased compared with that in non-diabetic mice, whereas ChIP assays also revealed reduced levels of H3K27Ac on of the ULK1 promoter sequences in diabetic mice [84]. 

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9. Histone Methylation and DKD (Table 4)

Histone methylation takes place in arginines, lysines, and histidines on histone tails [85]. Histone methylation modifications promote or repress gene transcription [86]. Lysine methylation is catalyzed by methyltransferases (KMTs) and is reversed by demethylases (KDMs) [87–89]. SET domain-containing enzymes are one class of KMTs [87]. 

KDM6A expression was increased and H3K27me2/3 levels were decreased in the kidneys of diabetic mice [90] and in hyperglycemia-treated podocytes and renal tubular cells [91,92]. In addition, in kidney tissues from patients with DKD, there was a reduction of the podocyte, glomerular cell, and tubular cell H3K27me3 [93]. Elevated H3K4me1 and H3K4me3 levels and decreases in H3K27me3 levels were detected in the kidneys of diabetic animals compared with non-diabetic controls [94]. 

Table 4. Effects of histone methylation on the pathogenesis of diabetic kidney disease.

10. Histone Methylation and Renal Inflammation in DKD

Palmitic acid (PA) stimulation decreased the enrichment of H3K27me3 on the promoters of IL1b and IL6, whereas the overexpression of KDM6A further decreased H3K27me3 levels on their promoters in renal mesangial cells [90]. In contrast, under PA treatment, KDM6A knockdown increased the enrichment of H3K27me3 on the promoters of IL1b and IL6 [90]. In vitro studies in renal tubular cells exposed to hyperglycemia suggest that the secretion of IL6 and MCP-1 increases and inflflammation stimulates the expression of KMT1A which catalyzes H3K9me3 to inhibit the transcription of inflammatory genes [99]. In another study, SET domain-containing protein 8 (SETD8) overexpression reduced hyperglycemia-induced IL-1β and IL-18 expression by attenuating hyperglycemia-induced MARK4 expression and inactivating the NLRP3 inflammasome, whereas H4K20me1, a downstream target of SETD8, was enriched in the MARK4 promoter region in HUVECs [100]. Furthermore, ChIP assays demonstrated that H4K20me1 levels were increased at the promoter region of E26 transformation-specific sequence transcription factor-1 (ESE-1), in HUVECs exposed to hyperglycemia [101]. Set7-induced enrichment of H3K4m1 on NF-kB p65 gene promoter led to the upregulation of ICAM-1, MCP-1, iNOS and cyclooxygenase-2 (COX-2) in peripheral blood monocytes [102]. Others reported that SET7/9 recruitment and H3K4me1 levels at MCP-1 promoters in diabetic mice were markedly higher compared with non-diabetic animals; the ER stress resulted in the enrichment of H3K4me1 at MCP-1 promoter in the kidneys of diabetic db/db mice through the preferential induction of SET7/9 [30]. Finally, renal hypertrophy in diabetes was linked to the upregulation of profifibrotic and proinflammatory genes and reduced levels of H3K27me3 and KMT6A in these gene promoters [103]. 

11. Histone Methylation and Renal Fibrosis in DKD 

The levels of H4K20me1, a downstream target of KMT5A, decreased in hyperglycemia-treated HUVECs and the levels of H4K20me1 were enriched in the promoter region of enolase 1 (ENO1), regulating the ENO1 levels and thereby inducing EndMT [104]. On the other hand, the expression of E-cadherin was decreased and its promoter methylation was upregulated with increasing KDM6A expression, but there was no relationship with the level of H3K27me2/3 in the E-cadherin promoter [92]. Hyperglycemia decreased KMT1A and histone H3K9me3 levels in the FN and p21 gene promoters [105]. On the other hand, the augmented expression of KMT1A increased the H3K9me3 levels in the FN and p21 promoters and protected against hyperglycemia-induced cell hypertrophy [105]. Hyperglycemia increased levels of KMT6A, resulting in the enrichment of H3K27me3 at the deptor promoter leading to decreased deptor expression, which led to the activation of mTORC1 and mTORC2, controlled mesangial cell hypertrophy and FN and PAI-1 expression [96]. In accordance with these findings, KMT6A inhibited mesangial cell proliferation and fibrosis-related protein expression in hyperglycemia-treated mesangial cells by downregulating hairy and enhancer of split 1 (HES1) expression; a ChiP assay showed that the KMT6A and H3K27me3 levels were increased in the HES1 promoter and enrichment was intensified by KMT6A overexpression [97]. Moreover, EZH2 knockdown signifificantly decreased the levels of H3K27me3 and downregulated the levels of smooth muscle alpha-actin (α-SMA), collagen I, and FN in rat renal interstitial fibroblast cells, whereas the silencing of KMT6A repressed the TGFβ1-stimulated expressions of α-SMA, collagen I, and FN [28]. In animal models of type 1 diabetes mellitus, the levels of H3K27m3 were reduced in MCP-1, vimentin and the fibrosis marker Fsp1 genes, while the levels of H3K4m2 were increased [106]. More recently, it was reported that histone H3 K79 methyltransferase Dot1l has an antifibibrotic effect by repressing Edn1, which encodes endothelin-1 [95]. Moreover, Dot1l interacts with HDAC2 to regulate Edn1 transcription [95]. Notably, HDAC2 was also shown to protect against renal ischemia/reperfusion injury by suppressing Edn1 transcription [98]. 

12. Histone Methylation and Oxidative Stress in DKD

In the kidneys of diabetic mice, hyperglycemia-induced Txnip expression was associated with the stimulation of activating histone marks H3K4me3 and H3K4me1, as well as with a decrease in the repressive histone mark H3K27me3 at the promoter of the gene [95]. In another study, KMT6A downregulated TxnIP expression through H3K27me3 enrichment in the promoter region of the transcription factor paired box 6 (Pax6), whereas the depletion of KMT6A led to an increase in the hyperglycemia-induced reactive oxygen species (ROS) levels and cellular death [98]. In addition, the depletion or inhibition of KMT6A attenuated the increase of ROS in hyperglycemia-treated human renal tubular epithelial cells, while the KMT6A knockdown attenuated the reduced expression of silent information regulator 1 (SIRT1) by hyperglycemia treatment [107]. The restoration of SIRT1 expression was in line with the elimination of H3K27me3 from the SIRT1 promoter and the inhibition of intracellular ROS levels [107].

13. Histone Methylation and Glomerular and Mesangial Hypertrophy in DKD 

TGF-β1 stimulated the expression of the p21 gene in rat mesangial cells, while the levels of H3K9me2/3 and H3K4me1/2/3 at the p21 gene promoter were correlated with p21 gene expression [32]. Similarly, the reduced H3K9me2 level in the p21 gene promoter in the glomeruli of type 1 diabetic rats was inversely correlated with p21 gene upregulation [108]. The increased H3K4me3 level in secreted phosphoprotein 1 (Spp1), the osteopontin gene, promoter were associated with Spp1 gene enhanced expression in hyperglycemia-treated human mesangial cells, whereas the levels of histone marks were linked to increases of Spp1 expression in animal studies [94]. Diminished podocyte H3K27me3 was correlated with glomerular injury while H3K27me3 controlled Notch signaling and podocyte dedifferentiation [93]. 

14. Histone Methylation and Other Manifestations of DKD 

SIRT-6 induction of activated protein kinase (AMPK) signaling, through H3K9 and H3K56, contributed to hyperglycemia-induced mitochondrial dysfunction and apoptosis in podocytes [109]. In another study, ChIP assays demonstrated the enrichment of H3K4me1 levels at the MAP4K3 gene and the upregulation of MAP4K3 in diabetic mice [110]. MAP4K3 knockdown decreased HYPERGLYCEMIA-induced apoptosis while MAP4K3 downregulation counteracted the expression of apoptosis markers [110]. Histone H2AK119 and H2BK120 ubiquitination regulated H3K4Me2 and H3K9Me2 chromatin marks by modifying the expression of their respective HMTs, SET7/9 and KMT1A [111]. The increased expression of SET7/9 and decreased expression of KMT1A could be associated with the increased enrichment of H3K4Me2 and decreased H3K9Me2 level at Collagen Type I Alpha 1 Chain (Col1a1) gene promoter and increased Col1a1 gene expression in the diabetic kidneys [111]. 

15. Conclusions 

Histone modification appears to play an important role in the pathogenesis of DKD. Indeed, histone acetylation and methylation are implicated in the propagation of inflammation, oxidative stress, and fibrosis in the kidney. Even though the exact mechanism(s) through which impaired epigenetic landscape contributes to DKD is still unclear, it appears that an altered enhancer landscape plays an important role [112–114]. It remains to be established whether targeting this pathway might prevent the development or delay the progression of DKD. Of note, it is well-established that DKD is associated with an increased risk for CVD [115]. In this context, somatic mutations, particularly in DNA methyltransferase 3 alpha and TET methylcytosine dioxygenase 2, are also implicated in the pathogenesis of both atherosclerosis and DKD, partly by a pro-inflammatory effect [116,117]. 

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