Transient High-Glucose Stimulation Induces Persistent Inflammatory Factor Secretion from Rat Glomerular Mesangial Cells via an Epigenetic Mechanism

Abstract

Background/Aims: Diabetic nephropathy is the one of the most serious microvascular complications of diabetes mellitus, and “metabolic memory” plays a vital role in the development of diabetic complications. To investigate the effect of epigenetics on metabolic memory, we analyzed the impact of transient high-glucose stimulation on the secretion of inflammatory factors from rat glomerular mesangial cells. Methods: Rat glomerular mesangial cells (HBZY-1) were divided into three groups: high-glucose group (25 mM glucose), hypertonic group (5.5 mM glucose+19.5 mM mannitol), and normal-glucose control group (5.5 mM glucose). Mesangial cells were cultured in high-glucose, hypertonic, and normal-glucose media for 24 h and transitioned to normal-glucose culture for 24, 48, and 72 h. Then, protein, mRNA, and supernatants were harvested. The expression of monomethylated H3K4 was determined by western blot analysis, and the expression of the NF-κB subunit p65 and histone methyltransferase set7/9 was determined by quantitative real-time PCR. The expression of monocyte chemoattractant protein 1 (MCP-1) and vascular cell adhesion molecule 1 (VCAM-1) was detected by an enzyme-linked immunosorbent assay. Results: Compared with the control group, H3K4me1 expression was upregulated after transient high-glucose stimulation, gradually downregulated in the following 48 h (P < 0.05), and reached the level of the control group at 72 h (P > 0.05). The expression of set7/9 was increased after 24 h of high-glucose stimulation and the following 24 h and 48 h (P < 0.05); it then returned to the level of the control group at 72 h. Compared with the control group, the increased expression of p65, VCAM-1, and MCP-1 was sustained for at least 72 h in the high-glucose group. Conclusion: Transient high-glucose stimulation can induce the persistent secretion of inflammatory factors from rat glomerular mesangial cells via histone modification.

Oligomeric S100A4 Is Associated With Monocyte Innate Immune Memory and Bypass of Tolerance to Subsequent Stimulation With Lipopolysaccharides

“…Methylation of lysine and arginine residues also can result in transcriptional activation. For instance, in rats, histone methylation is associated with persistent release of pro-inflammatory cytokines (35). Particularly interesting are the increased transcription of PR/SET domain proteins (PRDMs) encoding for histone methyltransferases.…”

The Role of Chemokines and Chemokine Receptors in Diabetic Nephropathy

“…TGF-β1 also increases CCL2 and MCP-1 induced protein-1 (MCPIP1), a suppressor of microRNA (miR)-146a via the ErbB4/epidermal growth factor receptor signaling pathway [36]. In glomerular mesangial cells, the up-regulated expression of endothelial vascular cell adhesion protein 1 (VCAM-1) and CCL2 can be sustained for at least 72 h under high glucose conditions [37]. Advanced glycation end products (AGEs) increase the expression of intercellular adhesion molecule 1 (ICAM-1) and CCL2 through the member A Rho kinase (RhoA/ROCK) signaling pathway [38].…”

METTL3 promotes PGC-1α transcription and alleviates mitochrondrial dysfunction of diabetic nephropathy by targeting lncRNA TUG1 m6A modification

“…The distribution of m 6 A has tissue specificity, and kidney is one of the most distributed organs of m 6 A [11] . m 6 A is catalyzed by the "writer"-methyltransferase complex (METTL3, METTL14, WTAP) on the consensus motif "RRACH" (R=G/A; H=A/C/U) [12] . On the contrary, the "erasers" -demethylase (ALKBH5 and FTO) can "erase" m 6 A on RNA [12] .…”

“…m 6 A is catalyzed by the "writer"-methyltransferase complex (METTL3, METTL14, WTAP) on the consensus motif "RRACH" (R=G/A; H=A/C/U) [12] . On the contrary, the "erasers" -demethylase (ALKBH5 and FTO) can "erase" m 6 A on RNA [12] . "Reader" -modification recognition protein can function through a direct or indirect combination of RNA, making the methylated RNA to be functionalized, including translation, RNA stability, selective editing, RNA processing, nuclear transportation, microRNA binding, and RNA-protein interaction [13] .…”