Long Non-coding RNA ENST00000453774.1 Confers an Inhibitory Effect on Renal Fibrosis by Inhibiting miR-324-3p to Promote NRG1 Expression

Abstract

Progressive or chronic renal diseases arise from a process of destructive renal fibrosis. Therefore, the molecular basis of renal fibrosis has attracted increasing attention. In this investigation, we set out to elucidate the potential interaction among long non-coding RNA ENST00000453774.1 (lncRNA 74.1), microRNA-324-3p (miR-324-3p), and NRG1, and to investigate their roles in the context of cellular autophagy and renal fibrosis. We collected 30 renal fibrosis tissue samples for analysis. In other studies, HK-2 cells were stimulated with TGF-β1 to induce a cell model of renal fibrosis, followed by alteration on the expression of lncRNA 74.1, miR-324-3p, or NRG1, or by the addition of AKT activator SC79 in the HK-2 cells. The expression levels of lncRNA 74.1, miR-324-3p, NRG1, autophagy-related proteins (ATG5, ATG7, LC3II/I, and P62), and the corresponding fibrosis markers (Collagen I, Fibronectin, and α-SMA) were subsequently determined using various assay methods. In addition, the proportion of LC3 positive cells and number of autophagosomes were recorded. Results revealed that lncRNA 74.1 and NRG1 were poorly expressed and miR-324-3p was highly expressed in renal fibrosis tissues and modeled cells. LncRNA 74.1 could bind to miR-324-3p, which led to upregulated NRG1 expression and inhibition of the PI3K/AKT signaling pathway. Meanwhile, overexpression of lncRNA 74.1 or down-regulation of miR-324-3p increased the levels of ATG5, ATG7, LC3II, and LC3I, and decreased levels of P62, Collagen I, Fibronectin, and α-SMA, accompanied by elevated proportions of LC3 positive cells and autophagosomes. Findings concur in showing that lncRNA 74.1 could induce cellular autophagy and alleviate renal fibrosis by regulating the miR-324-3p-mediated NRG1/PI3K/AKT axis. This axis may thus present a potential molecular target in renal fibrosis treatment.

Diagnostic potential of NRG1 in benign nerve sheath tumors and its influence on the PI3K-Akt signaling and tumor immunity

“…This type of interaction not only regulates the proliferation and survival of cells, but also influences the immune microenvironment, particularly the infiltration and function of M2 macrophages and neutrophils [ 50 ]. By studying in vitro cell line models, it has been discovered that the downregulation of NRG1 or the use of PI3K/AKT inhibitors can effectively impede cell proliferation and migration, while inducing apoptosis [ 51 ]. In contrast, the utilization of PI3K/AKT signaling agonists enhances the proliferative and migratory abilities of cells, while decreasing the rate of apoptosis [ 52 ].…”

“…This study unequivocally demonstrates the significant role of NRG1 in this process. Knocking down NRG1 or using PI3K/AKT inhibitors resulted in a decrease in tumor count and an increase in overall survival in PDX mouse models [ 51 ]. Specifically, the proliferative capacity of cells decreases, the rate of apoptosis increases, while the number of M2 macrophages decreases, and the number of neutrophils increases [ 54 ].…”

Comprehensive analyses of the microRNA–messenger RNA–transcription factor regulatory network in mouse and human renal fibrosis

“…In recent years, increasing evidence has demonstrated that energy metabolism plays a major regulatory role in the progression of RF ( Lan et al, 2016 ; Liu et al, 2017 ). Autophagy dysfunction is implicated in the pathogenesis of acute kidney injury and RF diseases ( Nam et al, 2019 ; Yang et al, 2020b ; Tang et al, 2021 ). Existing research further indicates that in RF, the process of autophagy may either promote it by contributing to tubular atrophy and decomposition or prevent it by improving intracellular degradation of excessive type I collagen mediated by TGF-β1 ( He et al, 2014 ).…”

Long Noncoding RNA LINC00467: Role in Various Human Cancers

“…( Yan et al, 2022 ) Besides MIR17HG also inhibits non-small cell lung cancer via functioning as a ceRNA of miR-142-3p. ( Wei et al, 2020 ) Through this regulatory mode, lncRNAs are widely involved in the course of various diseases, including thyroid cancer ( Guo et al, 2021 ), renal fibrosis ( Tang et al, 2021 ), atherosclerotic plaques ( Ann et al, 2021 ), among others.…”