Exosomal let‐7b‐5p deriving from parietal epithelial cells attenuate renal fibrosis through suppression of TGFβR1 and ARID3a in obstructive kidney disease

As renal progenitor cells, parietal epithelial cells (PECs) have demonstrated multilineage differentiation potential in response to kidney injury. However, the function of exosomes derived from PECs has not been extensively explored. Immunofluorescent staining of Claudin‐1 was used to identify primary PECs isolated from mouse glomeruli. Transmission electron microscopy, nanoparticle tracking analysis, and western blotting were used to characterize the properties of PECs‐derived exosomes (PEC‐Exo). The therapeutic role of PEC‐Exo in tubulointerstitial fibrosis was investigated in the unilateral ureteral obstruction (UUO) mouse model and TGF‐β1‐stimulated HK‐2 cells. High‐throughput miRNA sequencing was employed to profile PEC‐Exo miRNAs. One of the most enriched miRNAs in PEC‐Exo was knocked down by transfecting miRNA inhibitor, and then we investigated whether this candidate miRNA was involved in PEC‐Exo‐mediated tubular repair. The primary PECs expressed Claudin‐1, PEC‐Exo was homing to obstructed kidney, and TGF‐β1 induced HK‐2 cells. PEC‐Exo significantly alleviated renal inflammation and ameliorated tubular fibrosis both in vivo and in vitro. Mechanistically, let‐7b‐5p, highly enriched in PEC‐Exo, downregulated the protein levels of transforming growth factor beta receptor 1(TGFβR1) and AT‐Rich Interaction Domain 3A(ARID3a) in tubular epithelial cells (TECs), leading to the inhibition of p21 and p27 to restoring cell cycle. Furthermore, administration of let‐7b‐5p agomir mitigated renal fibrosis in vivo. Our findings demonstrated that PEC‐derived exosomes significantly repressed the expression of TGFβR1 and ARID3a by delivering let‐7b‐5p, thereby alleviating renal fibrosis. This study provides novel insights into the role of PEC‐Exo in the repair of kidney injury and new ideas for renal fibrosis intervention. In brief, this study is the first to report that PEC‐derived exosome therapy can alternate renal inflammation and fibrosis in a UUO mouse model. PEC exosomes are enriched with let‐7b‐5p, which reduces renal fibrosis by targeting TGFBRI and ARID3a. Moreover, the direct administration of let‐7b‐5p agomir in vitro also mitigated renal fibrosis in UUO mice.