Exosomal miR-21 from tubular cells contributes to renal fibrosis by activating fibroblasts via targeting PTEN in obstructed kidneys

Abstract

Rationale: Ureteral obstruction-induced hydronephrosis is associated with renal fibrosis and progressive chronic kidney disease (CKD). Exosome-mediated cell-cell communication has been suggested to be involved in various diseases, including renal fibrosis. However, little is known regarding how exosomes regulate renal fibrosis in obstructed kidneys. Methods: We first examined the secretion of exosomes in UUO (unilateral ureteral obstruction) mouse kidneys and TGF-β1-stimulated tubular epithelial cells (NRK-52E). Exosomes from NRK-52E cells were subsequently harvested and incubated with fibroblasts (NRK-49F) or injected into UUO mice via the tail vein. We next constructed Rab27a knockout mice to further confirm the role of exosome-mediated epithelial-fibroblast communication relevant to renal fibrosis in UUO mice. High-throughput miRNA sequencing was performed to detect the miRNA profiles of TGFβ1-Exos. The roles of candidate miRNAs, their target genes and relevant pathways were predicted and assessed in vitro and in vivo by setting specific miRNA mimic, miRNA inhibitor, siRNA or miRNA LNA groups. Results: Increased renal fibrosis was associated with prolonged UUO days, and the secretion of exosomes was markedly increased in UUO kidneys and TGF-β1-stimulated NRK-52E cells. Purified exosomes from TGF-β1-stimulated NRK-52E cells could activate fibroblasts and aggravate renal fibrosis in vitro and in vivo . In addition, the inhibition of exosome secretion by Rab27a knockout or GW4869 treatment abolished fibroblast activation and ameliorated renal fibrosis. Exosomal miR-21 was significantly increased in TGFβ1-Exos compared with Ctrl-Exos, and PTEN is a certain target of miR-21. The promotion or inhibition of epithelial exosomal miR-21 correspondingly accelerated or abolished fibroblast activation in vitro , and renal fibrosis after UUO was alleviated by miR-21-deficient exosomes in vivo through the PTEN/Akt pathway. Conclusion: Our findings reveal that exosomal miR-21 from tubular epithelial cells may accelerate the development of renal fibrosis by activating fibroblasts via the miR-21/PTEN/Akt pathway in obstructed kidneys.

Tumor-Derived Extracellular Vesicles Regulate Cancer Progression in the Tumor Microenvironment

“…In addition, EVs isolated from human vascular endothelial cells contain some cardioprotective proteins, which contribute to promoting human myocardium survival after ischemia-reperfusion injury ( Yadid et al, 2020 ). Vesicular miR-21 derived from tubular epithelial cells stimulates fibroblast and subsequently causes renal fibrosis in vivo ( Zhao S. et al, 2021 ). Vesicular lncRNA-SOX2OT from non-small cell lung cancer (NSCLC) cells induces osteoclast differentiation and promotes bone metastasis ( Ni et al, 2021 ).…”

Mesenchymal Stem Cells Alleviate Renal Fibrosis and Inhibit Autophagy via Exosome Transfer of miRNA-122a

“…Fourthly, tubular epithelial cells would be ideal to study the MSCs in fibroblast cells. Nonetheless, it has been reported that in addition to tubular epithelial cells, glomerular mesangial cells and kidney interstitial fibroblasts cells are also involved in the pathogenesis of kidney fibrosis [ 36 , 37 ]. It would be necessary to explore the effect of MSCs and miRNA-122a-transfected MSCs in these cell line models in the future.…”

What do we actually know about exosomal microRNAs in kidney diseases?

“…In unilateral ureteral obstructed (UUO) mouse kidneys and TGF-β-stimulated tubular cells, exosomal miR-21 levels are up-regulated. Increased miR-21 can accelerate the development of renal fibrosis by activating fibroblasts via the miR-21/PTEN/Akt pathway ( Zhao et al, 2021 ). Similarly, exosomes from miR-374a-5p-modified mesenchymal stem cells (MSCs) can inhibit TGF-β1-induced fibrosis by regulating the MAPK6/MK5/YAP axis ( Liang et al, 2022 ).…”