Epigenetics and Inflammation in Diabetic Nephropathy

Abstract

Diabetic nephropathy (DN) leads to high morbidity and disability. Inflammation plays a critical role in the pathogenesis of DN, which involves renal cells and immune cells, the microenvironment, as well as extrinsic factors, such as hyperglycemia, chemokines, cytokines, and growth factors. Epigenetic modifications usually regulate gene expression via DNA methylation, histone modification, and non-coding RNAs without altering the DNA sequence. During the past years, numerous studies have been published to reveal the mechanisms of epigenetic modifications that regulate inflammation in DN. This review aimed to summarize the latest evidence on the interplay of epigenetics and inflammation in DN, and highlight the potential targets for treatment and diagnosis of DN.

Keywords: DNA methylation; diabetic nephropathy; epigenetics; histone modifications; inflammation; non-coding RNAs.

FIGURE 1

Interaction of immune cells, kidney intrinsic cells and epigenetic modifications. DNA methylation, histone modifications, and non-coding RNA modifications activate inflammatory pathways by interactions of immune cells and kidney intrinsic cells. OS, oxidative stress; ROS, reactive oxygen species; HG, high glucose; Ang II, angiotensin II; AGE-RAGE, advanced glycation end-products-receptor for advanced glycation end products; IL, interleukin; TNF, tumor necrosis factor; MCP-1, monocyte chemoattractant protein 1; NF-κB, nuclear factor-κB; JAK-STAT, Janus kinase/signal transducer and activator of transcription; NRF2, Nuclear Factor-2 Erythroid Related Factor; NLRP, NOD-like receptor pyrin domain-containing protein.

FIGURE 2

The inflammatory pathways involved in the DN process. High glucose or stimulating factors cause the activation of multiple pathways, including P38/MAPK, PI3K/AKT, TLR4/NLRP3 and the novel CRP/DPP4/CD32b, which all further activate NF-κB pathway, and transcriptionally promote the expression of multiple inflammatory cytokines to enhance inflammation. SMAD7 can inhibit NF-κB activity. NRF2 has anti-inflammatory and antioxidant functions in DN. In addition, JAK/STAT pathway induces IL-6 to promote the inflammatory response in DN. DN, diabetic nephropathy; IL, interleukin; TNF, tumor necrosis factor; NF-κB, Nuclear factor-κB; MCP-1, monocyte chemoattractant protein-1; STAT, Signal transducer and activator of transcription; NRF2, Nuclear factor-2 erythroid related factor; NLRP3, NOD-like receptor protein 3; ROS, reactive oxygen species; DPP4, dipeptidyl peptidase-4; MAPK, mitogen-activated protein kinase; JAK2, Janus kinase; TLR4, Toll-like receptors 4; CRP, C-reactive protein; AGE, advanced glycation end product; RAGE, Receptor for advanced glycosylation end products; Ang II, angiotensin II; TGF, Transforming growth factor.

FIGURE 3

The roles of DNA methylation and histone modification in the DN process. High glucose or stimulating factors cause DNA methylation and histone modification. DNA methylation is mainly regulated by DNMTs. MIC-1 and TIIA inhibits DNA methylation and reduces inflammation in DN. In the processes of histone modification, SET7/9 regulates H3K4 methylation, UTX regulates H3K27 demethylation, HAT promotes histone acetylation, and HDAC4/9 promotes histone deacetylation. The above processes regulate inflammatory genes, in turn affects the inflammatory response in DN. DN, diabetic nephropathy; DNMTs, DNA methyltransferases; UTX, ubiquitously transcribed tetratricopeptide repeat, X chromosome; HAT, histone acetyltransferases; HDAC, histone deacetylase; NF-κB, Nuclear factor-κB; MCP-1, monocyte chemoattractant protein-1; STAT1, Signal transducer and activator of transcription 1.