miR‐218 regulates diabetic nephropathy via targeting IKK‐β and modulating NK‐κB‐mediated inflammation

Abstract

Diabetic nephropathy (DN) is a common clinically relevant complication of diabetes that is associated with damage to the capillaries, yet the etiology of this condition remains unclear. Nuclear factor-kappa B (NF-κB) activation is known to be associated with DN-related inflammation and disease progression. Recent work indicated that microRNAs are diagnostic biomarkers of DN progression associated with inflammation in the progression of DN. miR-218 is known to play key regulatory roles in certain cancers in humans, while its influence on DN pathology remains uncertain.The present study, therefore, sought to assess how miR-218 influences the progression of disease in both a rat streptozotocin-induced model of DN and as well as an in vitro model system in which mouse podocytes were stimulated with high glucose levels. We found miR-218 to be markedly downregulated in both model systems relative to appropriate controls, and this downregulation was associated with IKK-β upregulation. In DN rat model, overexpressing miR-218 was sufficient to reduce renal injury. We further determined that podocyte proliferation was markedly impaired by glucose treatment, leading to the apoptotic death of these cells, and miR-218 mimics were able to reduce these phenotypes. Overexpressing miR-218 also significantly dampened inflammatory responses in this model system, as evidenced by reduced tumor necrosis factor-α, interleukin-6 (IL-6), IL-1β, and MCP-1 levels. We then confirmed that miR-218 targeting the messenger RNA encoding IKK-β using a dual-luciferase reporter assay. Together, our results provide clear evidence that miR-218 regulate NF-κB-mediated inflammation, which is central to DN progression.

DACH1, a novel target of miR-218, participates in the regulation of cell viability, apoptosis, inflammatory response, and epithelial-mesenchymal transition process in renal tubule cells treated by high-glucose

“…Consistent with the above findings, we also observed that miR-218 was upregulated in DKD and could reduce cell viability in HGtreated renal tubule cells, which indicated that depletion of miR-218 may protect cells from injury during the development of DKD. However, Li et al, using a rat streptozotocin-induced model of DKD and in vitro HGstimulated mouse podocytes, demonstrated that miR-218 was markedly downregulated in both model systems relative to appropriate controls [19]. We hypothesized that many factors, such as different inducers, and animal or human cells, contributed to this phenomenon.…”

“…The mechanism of action of miRNA is mediated by binding target mRNA to inhibit mRNA translation or degrade miRNAbound mRNA, thus inhibiting protein synthesis [15]. By a literature review, it has also revealed that numerous miRNAs are involved in the inflammation of DKD, including miR-218 [16][17][18][19]. It is noted that overexpression of miR-218 can reduce renal injury in a streptozotocin-induced rat model of DKD and can inhibit inflammatory response in the high glucose (HG) induced mouse podocytes by targeting mRNA encoding IKK-b [20].…”

Noncoding RNAs in Diabetic Nephropathy: Pathogenesis, Biomarkers, and Therapy

“…A recent study showed that in a DN rat model, overexpressing miR-218 was sufficient to reduce renal injury through regulating NF-κB-mediated inflammation. Moreover, they confirmed that miR-218 targets the messenger RNA (mRNA) encoding IKK-β [40]. [46].…”

The novel circ_0028171/miR-218-5p/IKBKB axis promotes osteosarcoma cancer progression

“…Regarding miR-218, Yao et al [ 22 ] reported that microRNA-218 inhibited the viability and accelerates the apoptosis in ARPE-19 cells by directly targeting RUNX2. Moreover, the experimental research showed [ 23 ] that miR-218 was markedly downregulated in diabetic nephropathy rat model, and overexpressed miR-218 markedly reduced inflammatory responses, detected by measuring the level of TNF-α, IL-6, IL-1β, and MCP-1. Previously, it [ 24 ] has been reported that lncRNA CCAT1 serves as a microRNA-218 sponge to induce Gefitinib Resistance in NSCLC by Targeting HOXA1.…”