Epigenetics and endoplasmic reticulum in podocytopathy during diabetic nephropathy progression

Abstract

Proteinuria or nephrotic syndrome are symptoms of podocytopathies, kidney diseases caused by direct or indirect podocyte damage. Human health worldwide is threatened by diabetic nephropathy (DN), the leading cause of end-stage renal disease (ESRD) in the world. DN development and progression are largely dependent on inflammation. The effects of podocyte damage on metabolic disease and inflammatory disorders have been documented. Epigenetic and endoplasmic reticulum (ER) stress are also evident in DN. Targeting inflammation pathway and ER stress in podocytes may be a prospective therapy to prevent the progression of DN. Here, we review the mechanism of epigenetics and ER stress on podocyte inflammation and apoptosis, and discuss the potential amelioration of podocytopathies by regulating epigenetics and ER stress as well as by targeting inflammatory signaling, which provides a theoretical basis for drug development to ameliorate DN.

Keywords: diabetic nephropathy; endoplasmic reticulum; epigenetics; inflammation signaling; podocyte.

Figure 1

Consequences of podocytopathies. Podocyte injury causes cellular and structural responses in the glomerulus. An injured podocyte has cytoplasmic blebs, protein droplets, and an expanded subpodocyte space. Foot process effacement is associated with actin derangement, which induces dysfunction of slit molecules. The injured podocyte detaches from the glomerular basement membrane, which is associated with abnormalities of adhesion molecules, coagulation cascade, chemokine receptor expression, and lipid peroxidation. These changes may depend on podocyte detachment but also on aberrant factors from injured podocytes. PECs, parietal epithelial cells; VEGF, vascular endothelial growth factor.

Figure 2

Histone modifications and DNA methylation in podocytopathies. Under normal conditions, Sirt6 inhibits the transcription of Notch1 and Notch4 by decreasing H3K9ac levels in the promoter regions of Notch1 and Notch4. METTL14 deficiency inhibits Sirt1 mRNA m6A modification, thereby increasing Sirt1 levels in normal podocytes. METTL3 modulates the m6A modification of TIMP2 in an IGF2BP2-dependent manner and exerts pro-inflammatory and -apoptotic effects. TIMP2, tissue inhibitor of metalloproteinase 2; IGF2BP2, insulin-like growth factor 2 mRNA binding protein 2.

Figure 3

Proposed mechanism of transcriptional activation of K4Me in podocytes. Crosstalk between normal and hyperglycemic conditions in DN. ORF, open reading frame; DBD, DNA-binding domain; H3K4Me3, trimethylation of lysine 4 on histone H3 protein subunit; PRE, Pax response elements; DACH1, Dachshund homolog 1; PTIP, Pax transactivation-domain interacting protein.

Figure 4

Regulatory interactions between epigenetic machinery and non-coding RNAs. DNMTs and HDACs are epigenetic mediators of DNA methylation and histone acetylation, which result in condensed-relaxed chromatin. lncRNAs and miRNAs modulate epigenetic mediators, thus regulating chromatin remodeling.

Figure 5

Mechanisms of ER stress-induced inflammation. Inositol-requiring enzyme 1α (IRE1α) and PKR-like ER kinase (PERK) activation induce inflammasome activation. (A) IRE1α activation and subsequent splicing of X-box binding protein 1 (Xbp1) produces the transcription factor XBP1s, which directly binds the promoters of tumor necrosis factor (TNF) and interleukin-6 (IL-6). (B) Regulated IRE1α-dependent decay (RIDD)-dependent degradation of miR-17, which in unstressed conditions represses thioredoxin-interacting protein (Txnip), increases the Txnip level, NLRP3 inflammasome activation, and IL-1β expression. (C) Activated IRE1α forms a complex with TNF receptor-associated factor 2 (TRAF2) to induce phosphorylation of Jun N-terminal kinase (JNK) and upregulation of proinflammatory genes via activated activator protein 1 (AP1). (D) IRE1α–TRAF2 complex recruits IκB kinase (IKK); subsequent phosphorylation and degradation of IκB releases nuclear factor-κB (NF-κB) for nuclear translocation. BiP, binding immunoglobulin protein. (E) Txnip can be induced by the PKR-like ER kinase (PERK)-activating transcription factor 5 (ATF5) pathway to induce inflammasome activation.

Figure 6

Activation of ATF6 pathway and abnormal IRE1 pathway may aggravate ER stress response. (A) Role of the IRE1 pathway in the ER stress response. Insulin signaling inhibits the interaction of XBP1s with the phosphatidylinositol 3-kinase (PI3K) regulatory subunits p-85α and p-85β, suppressing proinflammatory cytokine production. (B) Compounds such as emodin and chrysin inhibit PERK activation and decrease the Bax/Bcl-2 ratio in hyperglycemia, preventing podocyte apoptosis. (C) Insulin deficiency, insulin resistance, and hyperglycemia aggravate site 1 protease (S1P)- and S2P-mediated cleavage of ATF6α, allowing their fragments to translocate to the nucleus.

Figure 7

MicroRNAs with potential roles in podocytopathies. Hyperglycemia up- or down-regulates miRNAs in podocytes, resulting in podocytopathies. ↑ Indicate increased expression, ↓ Indicate decrease.

Figure 8

LncRNAs with potential roles in podocytopathies. Hyperglycemia up- or down-regulates lncRNAs in podocytes, resulting in podocytopathies.