A novel role of the miR‐152‐3p/ERRFI1/STAT3 pathway modulates the apoptosis and inflammatory response after acute kidney injury

Abstract

Acute kidney injury (AKI) is one of the most common and serious complications in the development of sepsis. Many microRNAs are closely related to the occurrence, development, and prognosis of sepsis AKI (but the effect and mechanism of miR‐152‐3p in it is unclear). Meanwhile, the ERBB receptor feedback inhibitor 1 (ERRFI1) has a negative regulatory effect on signal transducer and activator of transcription 3 (STAT3) phosphorylation on uterine epithelial cells. But, the relationship between miR‐152‐3p and renal function, inflammatory factors, prognosis in AKI, and the mechanism is not clear. Analyzing sepsis‐induced AKI rats and the cell model, our results revealed that miR‐152‐3p was upregulated in septic AKI patients and positively correlated with serum creatinine, urea nitrogen, interleukin 1β (IL‐1β) and tumor necrosis factor α (TNF‐α). Downregulation of miR‐152‐3p with the inhibitor could dramatically attenuate caspase‐3, bromodeoxyuridine and IL‐1β, and TNF‐α in the AKI rats' model. Furthermore, downregulation of miR‐152‐3p attenuated lipopolysaccharide‐induced apoptosis and inflammatory response in HK‐2 and HEK293 cells. To further explore the mechanisms, we found ERRFI1 was appreciably downregulated and STAT3 was upregulated in AKI, whereas ERRFI1 was radically upregulated and STAT3 was greatly downregulated after the addition of miR‐152‐3p inhibitor, no matter in vivo or in vitro. Summarily, our study confirmed that miR‐152‐3p could promote the expression of STAT3 by targeting ERRFI1, aggravate cell apoptosis and inflammatory response, and thereby aggravate kidney injury in sepsis AKI.

A novel genomic model for predicting the likelihood of delayed graft function in DCD kidney transplantation

“…More insights gained in the molecular pathophysiology of IR in DCD renal allografts would open a door to the understanding and management of DGF. Consistent with the observed alterations of the five genes in DCD kidneys during IR in this study, previous studies have suggested that the above genes are closely involved in the pathogenic process of IRI to some extent (27)(28)(29)(30)(31). The general information of the five genes and the potential correlations between their dysregulation and renal IRI or DGF occurrence have been properly discussed in the Appendix 1.…”

“…And Chen et al identified that ERRFI1, a known negative feedback regulator of EGFR, could reduce proinflammatory mediator production (such as TNF-α and IL-1β) by controlling excessive EGFR activation in LPS-induced endotoxemia or LPS-treated nucleus pulposus cells (46,47). Importantly, Ma et al reported that downregulation of ERRFI1 in AKI of sepsis targeted by miR-152-3p could promote the activation of the STAT3 signaling pathway, thereby aggravating cell apoptosis and the inflammatory response (31). It seems that both dysregulation of GOLPH3 and ERRFI1 in DCD kidneys may lead to disorder of EGFR expression resulting in enhanced renal IRI and DGF in DCD KT.…”

Targeting STAT3: A crucial modulator of sepsis

“…Besides, many microRNAs are closely associated with the occurrence, development of sepsis AKI. For example, miR-152-3p could promote the expression of STAT3 by targeting ERBB receptor feedback inhibitor 1 (ERRFI1) thus aggravating LPS-induced renal cell apoptosis and inflammatory response, attested by dramatically higher levels of caspase-3, IL-1β, TNF-α, BUN, and Scr (Ma et al, 2020).…”

Suppression of lncRNA GAS6-AS2 alleviates sepsis-related acute kidney injury through regulating the miR-136-5p/OXSR1 axis in vitro and in vivo

“…In this work, the experiments that have been carried out should be sufficient to draw a conclusion that inhibition of GAS6-AS2 had a protective effect on septic AKI. The purpose of cell experiment is to reveal the function and explore the corresponding mechanism, and in vivo experiment was also performed, which is in line with the idea of medical research: cell exploration first, then animal verification [ 52 , 53 ]. However, there are still some limitations to our study.…”