MiR‐874 alleviates renal injury and inflammatory response in diabetic nephropathy through targeting toll‐like receptor‐4

Abstract

Diabetic nephropathy (DN) is a kind of diabetic complication with capillary damage, and its pathogenesis remains obscure. Recently, microRNAs have been identified as diagnostic biomarkers in various diseases including DN. Toll-like receptor 4 (TLR4) contributes to inflammation, and it has been implicated in diabetes pathophysiology. This study was designed to investigate the role of miR-874 and TLR4 in a streptozotocin (STZ)-induced DN rat model and glucose-induced mouse podocyte model. In the current study, we reported that miR-874 was markedly downregulated in DN rats and glucose-induced mouse podocytes compared with the corresponding control groups with the activation of TLR4. In addition, we observed that overexpression of miR-874 was able to alleviate renal injury in DN rats. The cell counting kit (CCK-8) assay and 5-Ethynyl-2'-deoxyuridine (EdU) assay demonstrated that glucose simulation significantly inhibited podocyte proliferation and induced cell apoptosis, which can be reversed by miR-874 mimics significantly. Notably, miR-874 overexpression dramatically attenuated the inflammatory response, indicated by the decreased levels of interleukin-6, L-1β, and tumor necrosis factor α (TNF-α). Finally, the binding correlation between miR-874 and TLR4 was confirmed by carrying out dual-luciferase reporter assay in our study. It was found that overexpression of miR-874 depressed TLR4 levels in podocytes. These findings implied for the first time that the overexpression of miR-874 repressed glucose-triggered podocyte injury through targeting TLR4 and suggested that miR-874/TLR4 axis might represent a pathological mechanism of DN.

miR-874 ameliorates retinopathy in diabetic rats by NF-κB signaling pathway

“…Recent studies have revealed that miRNAs participate in the development and progression of DR and are involved in multiple pathogenesis of DR [14][15][16]. We found a site where miR-874 bound to the NF-κB p65 by the prediction on a bioinformatics website, and the down-regulation of miR-874 expression in rats with myocardial ischemia reperfusion injury exerted an inhibitory effect on inflammation and injury [17,18]. However, we did not found the relationship between miR-874 and DR.…”

MiR-770-5p facilitates podocyte apoptosis and inflammation in diabetic nephropathy by targeting TIMP3

“…MicroRNA-195 facilitated apoptosis of podocytes treated with high-glucose through elevating caspase activity for BCL2 insufficiency [29]. MiR-874 relieved podocyte injury in DN via regulating TLR4 expression [30]. MiR-320a facilitated DN development via targeting MafB and relieving Nephrin and Gpx3 [31].…”

Interactions Among Non-Coding RNAs in Diabetic Nephropathy

“…In DN patients, restoration of miR-374a expression in renal tubular epithelial cells prevented the inflammatory response (Yang et al, 2018b). Similarly, miR-874 negatively regulates the expression of Toll-like receptor-4 (Tlr4), and thus prevents the secretion of pro-inflammatory cytokines in DN mice (Yao et al, 2018). Another anti-inflammatory miRNA is the miR-455-3p that negatively regulates the expression of coil-containing protein kinase 2 (ROCK2), and consequently reduced the inflammatory cytokines and fibrosis markers in a human kidney cell line (Wu et al, 2018).…”

“…Similar to MALAT-1, pro-inflammatory lncRNA, GM6135 increases the expression of Tlr4, by competitive binding to miR-203-3p, thus further activates the secretion of pro-inflammatory cytokines in DN mice (Ji et al, 2019). Interestingly, miR-874 also negatively regulates the Tlr4 gene expression (Yao et al, 2018). Thus further works are needed to determine whether lncRNA GM6135 could interact with miR-874 and elevates TLR4 expression.…”