Visual Abstract

Background: Acute kidney injury (AKI) is a complex clinical disorder with sudden decay in renal function. Ischemia-reperfusion injury (IRI) has been regarded as the main etiology for the occurrence of AKI. MicroRNAs have been consistently shown to be involved AKI. Objectives: We aimed to investigate the role of miR-155 in AKI and its underlying mechanism. Methods: Ischemia-reperfusion (I/R)-induced AKI rat model and hypoxia-reoxygeneration (H/R)-induced NRK-52E cell model were established. The concentrations of serum creatinine and blood urea nitrogen were measured to evaluate renal function. Hematoxylin and eosin staining and TUNEL assay were performed to assess the severity of kidney injury. Additionally, quantitative real-time-PCR and western blot analysis were subjected to determine the expression of miR-155, TCF4, and apoptosis-related proteins, respectively. Moreover, cell proliferation and apoptosis were evaluated by Cell Counting Kit-8, bromodeoxyuridine, and flow cytometry analyses, respectively. Luciferase reporter assay was used to validate the direct targeting of TCF4 with miR-155. The protein levels of TCF4 and its downstream proteins in cells were measured by western blot. Results: The expression level of miR-155 was upregulated in both I/R-induced AKI rat model and H/R-treated NRK-52E cells. Moreover, overexpression of miR-155 promoted H/R-induced NRK-52E cells apoptosis and suppressed cell proliferation, while inhibition of miR-155 expression exerted opposite effects. Additionally, TCF4 was identified as a target of miR-155, of which expression was downregulated both in vivo and in vitro. Furthermore, the activity of Wnt/β-catenin signaling pathway was promoted following overexpression of TCF4 in NRK-52E cells, and this effect was attenuated by the increasing miR-155 expression. Conclusion: We demonstrated that miR-155 exacerbated AKI involving the targeting and regulation of TCF4/Wnt/β-catenin signaling pathway, indicating a novel regulatory network and elucidating a potential target for IRI-induced AKI treatment.

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