Knockdown of miR-214 Alleviates Renal Interstitial Fibrosis by Targeting the Regulation of the PTEN/PI3K/AKT Signalling Pathway

Abstract

The microRNA-214 (miR-214) precursor is formed by the DNM3 gene on human chromosome 1q24.3, which is encoded and transcribed in the nucleus and processed into mature miR-214 in the cytoplasm. Association of miR-214 with the interstitial fibrosis of the kidney has been reported in existing research. Renal interstitial fibrosis is considered necessary during the process of various renal injuries in chronic kidney disease (CKD). One of the important mechanisms is the TGF- (transforming growth factor-) β1-stimulated epithelial interstitial transformation (EMT). The specific mechanisms of miR-214-3p in renal interstitial fibrosis and whether it participates in EMT are worthy of further investigation. In this paper, we first demonstrated modulation of the downstream PI3K/AKT axis by miR-214-3p through targeting phosphatase and tension protein homologues (PTEN), indicating the miRNA’s participation in unilateral ureteral obstruction (UUO) nephropathy and TGF-β1-induced EMT. We overexpressed or silenced miR-214-3p and PTEN for probing into the correlation of miR-214-3p with PTEN and the downstream PI3K/AKT signalling pathways. According to the results of the study, miR-214-3p overexpression silenced PTEN, activated the PI3K/AKT signalling pathway, and exacerbated EMT induced by TGF-β1, while miR-214-3p knockdown had the opposite effect. In miR-214-3p knockdown mice, the expression of PTEN was increased, the PI3K/AKT signalling pathway was inhibited, and fibrosis was alleviated. In conclusion, miR-214-3p regulates the EMT of renal tubular cells induced by TGF-β1 by targeting PTEN and regulating the PI3K/AKT signalling pathway. Furthermore, miR-214-3p knockdown can reduce renal interstitial fibrosis through the PTEN/PI3K/AKT pathway.

Nephroprotective Effects of Cardamonin on Renal Ischemia Reperfusion Injury/UUO-Induced Renal Fibrosis

“…In response to acute or chronic kidney injury, the MAPK pathway was obviously activated as evidenced by the increased phosphorylation of P38, ERK1/2, and JNK, which exerts proinflammatory, proapoptotic, and profibrotic impacts during renal I/R injury and renal fibrosis. , Inhibiting the activation of the MAPK pathway was authenticated to significantly ameliorate AKI and renal fibrosis. ,, The enriched top 5 pathways of those 40 intersected genes in order are pathways in cancer, MAPK, PI3K-Akt, human cytomegalovirus infection, and chemical carcinogenesis-receptor activation pathways during KEGG enrichment analysis. The PI3K-Akt signaling pathway is not as consistent as the MAPK pathway in its role in renal I/R injury and renal fibrosis, whereas activating the PI3K-Akt pathway induced the process of TGF-β1-induced EMT and relieved renal I/R injury. , Previous studies revealed that CAD attenuated renal cyst enlargement, LPS-induced lung sepsis, and carrageenan-induced paw edema by inhibiting the MAPK signaling pathway. ,, The bioinformatic analyses and established studies seem to suggest that the MAPK signaling pathway participated in the regulation of renal I/R and UUO injuries during CAD administration. In our animal and cell models, CAD employment markedly mitigated the activation of MAPK NF-κB cascade to reduce renal I/R and UUO damage.…”

“…The PI3K-Akt signaling pathway is not as consistent as the MAPK pathway in its role in renal I/R injury and renal fibrosis, whereas activating the PI3K-Akt pathway induced the process of TGF-β1-induced EMT and relieved renal I/R injury. 9,23 Previous studies revealed that CAD attenuated renal cyst enlargement, LPS-induced lung sepsis, and carrageenan-induced paw edema by inhibiting the MAPK signaling pathway. 17,29,30 The bioinformatic analyses and established studies seem to suggest that the MAPK signaling pathway participated in the regulation of renal I/R and UUO injuries during CAD administration.…”

“…They were incubated in a constant-temperature incubator (5% CO 2 , 74% N 2 , 21% O 2 ) at 37 °C. The recombinant TGF-β1 protein was initially identified as a growth factor that induces the growth of rodent fibroblasts and was always selected to induce cells to construct in vitro fibrosis models of various diseases. , In order to induce renal fibroblasts in vitro, 5 ng/mL of TGF-β1 was selected to be added into cell plates followed by the administration of CAD (100 μM, dissolved in DMSO) 4 h later. HK-2 cells were collected for further experiments after 24 h of fibrosis induction.…”

Epithelial–mesenchymal plasticity in kidney fibrosis

“…For example, TGF‐β1‐induced EMT is mediated by microRNA‐214 (miR‐214) precursor (miR‐214‐3p; Hou et al, 2022). This microRNA downregulates phosphatase and tensin homolog and activates PI3K/AKT signaling pathway (Hou et al, 2022). TGF‐β also induces expression of alternative polyadenylation writer (cleavage stimulation factor 2 or CSTF2) in TECs (Tan et al, 2022).…”

“…TGF‐β1 can also activate the target genes via non‐Smad pathway (Batlle & Massague, 2019; Sheng & Zhuang, 2020; Xu et al, 2016). For example, TGF‐β1‐induced EMT is mediated by microRNA‐214 (miR‐214) precursor (miR‐214‐3p; Hou et al, 2022). This microRNA downregulates phosphatase and tensin homolog and activates PI3K/AKT signaling pathway (Hou et al, 2022).…”