Table 4.
Epigenetic modulation and relationship to key pathogenic processes in diabetic nephropathy.
| Injury | DNA or Protein Modification | Effect in Target Genes | Relation between Epigenetic Modification and Gene Target * | Sample/Model or Treatment | Ref. |
|---|---|---|---|---|---|
| Podocyte injury | ↑ DNA-methylation | ↓ GRIA3 | Causal | Human and murine podocytes/HG | [65] |
| ↑ DNA-methylation | ↓ Nphs1 | Association | Kidney/db/db mice Kidney/STZ rat and db/db mice |
[67] [68] |
|
| ↓ H3K27m2 | ↑ Pax6 | Causal | Murine podocytes/HG Kidney/STZ rats |
[100] | |
| Inflammation | ↑ DNA-methylation | ↓ negative regulators of mTOR | Association | PBMCs/db/db mice | [81] |
| ↓ H3K27m2 | ↑ CCL2 | Association | Rat mesangial cells/ TGF-β1 Kidney/OVE26 mice (T1D) |
[99] [97] |
|
| ↑ H3K4 m1/m2/m3 | ↑ inflammatory genes ↑ inflammatory genes ↑ Mcp-1 |
Causal Association Causal |
Macrohages/diabetic mice Monocytes /diabetic patients Kidney/OVE26 mice (T1D) |
[104] [105] [97] |
|
| ↑ H2BK5ac | ↑ Mme | Association | Kidney/STZ rats | [119] | |
| ↑ H3K18ac | |||||
| ↑ H3K9/14ac | ↑ TNFα and COX-1 | Association | Monocytes/Diabetic human | [120] | |
| ↑ Txnip | Association | Kidney/Diabetic mice | [121] | ||
| Human and mouse mesangial cells/HG | |||||
| ↑ Mcp-1 | Association | Kidney/db/db mice Murine mesangial cells/HG |
[106] | ||
| ↑ H4K5/8/12ac | ↑ TNFα and COX-1 | Association | THP-1 monocytes/ HG | [120] | |
| Fibrosis ↑ EMT | ↓ DNA-methylation | ↑ MMP9 | Association | Human podocytes/HG Kidney/STZ rat |
[66] |
| ↑ DNA-methylation | ↓ KLF4 | Causal | Human proximal tubular cells/ TGF-β1 | [79] | |
| ↑ H3K4m2 | ↑ Fsp1 | Association | Kidney/STZ rats | [97] | |
| ↓ H3K27m3 | |||||
| Fibrosis ↑ ECM | ↑ DNA-methylation | ↓ Trim13 | Causal | Kidney/STZ rat and db/db mice | [71] |
| ↓ DNA-methylation | ↑ MIOX | Association | Human proximal tubular cells/HG Kidney/STZ rat |
[64] | |
| ↓ H3K9m3 | ↑ Fn-1, p21 | Causal | Murine mesangial cells/HG | [101] | |
| ↑ H3K4m1/2/3 ↓ H3K9m2/3 |
↑ ECM-associated genes | Causal Association |
Rat mesangial cell/HG | [103] |
|
| ↑ H3K9/14ac | ↑ Fn-1 and Pai-1 | Association | Kidney/STZ-induced diabetic mice | [113] | |
| ↑ Pai-1 and p21 | Association | Rat mesangial cells/HG | [114,115] | ||
| ↑ Pai-1 and Rage | Causal | Kideny/db/db mice Murine mesangial cells/HG |
[106] | ||
| ↑ H4Kac | ↑ Col1A2 | Causal | Murine mesangial cells/TGF-β | [118] | |
| Fibrosis (TGFβ1) | ↓ DNA-methylation | ↑ Tgf-β1 | Association | Kidney/db/db mice | [74] |
| Causal | Kidney/db/db mice Human mesangial cells/HG |
[75] |
* Association: Changes in epigenetic markers was associated with changes in gene expression. Causal: potentially causal as induction of changes in epigenetic markers was followed by changes in gene expression and both increased and decreased epigenetic markers had coherent impact on gene expression. HG: high glucose concentration. PBMC: peripheral blood mononuclear cells.