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Abstract: FR-PO999

Tubular Epithelial Cell-Derived Exosomal MiRNA-19b-3p Promotes M1 Macrophage Activation in Kidney Injury

Session Information

Category: Pathology and Lab Medicine

  • 1601 Pathology and Lab Medicine: Basic

Author

  • Feng, Ye, Zhongda Hospital, Southeast university, Nanjing, China
Background

Tubulointerstitial inflammation is a common characteristic for acute and chronic kidney injury. However, the mechanism by which the initial injury on tubular epithelial cells (TECs) drives interstitial inflammation remains unclear. Here we set out to characterize the miRNA profile of kidney exosomes and aim to explore the role of exosomal miRNAs derived from TECs in the development of tubulointerstitial inflammation.

Methods

Exosomes were isolated from kidney and characterized via electron microscopy (EM) and nanoparticle analysis(NTA). We examined profiles of miRNAs in kidney exosomes from LPS-induced kidney injury model by Exiqon microarray. Putative targets of miRNA were predicted by TargetScan. Chronic proteinuric kidney disease model was induced by adriamycin(ADR) injection. Exosomes purified from TECs were added to macrophages or intrarenal injected to mice to determine its effects both in vitro and in vivo.

Results

Serum creatinine and urine albumin to creatinine ratios were significantly increased in LPS treated mice compared with controls. Histologically, the tubular epithelial cell injury, protein cast and CD68+ macrophage infiltration was found in LPS injected mice. EM and NTA confirmed the typical characteristic of exosomes. Global miRNA expression profiling on renal exosomes was examined in LPS-induced AKI model and miR-19b-3p was identified as the most remarkable miRNA increased in TEC-derived exosomes compared with controls. Similar results were found in ADR-induced chronic proteinuric kidney disease model in which exosomal miR-19b-3p was markedly released. Interestingly, once released, TEC-derived exosomal miR-19b-3p was internalized by macrophages, leading to M1 phenotype polarization through targeting NF-κB/SOCS-1. Importantly, the pathogenic role of exosomal miR-19b-3p in initiating renal inflammation was revealed by the ability of adoptive transfer of purified TEC-derived exosomes to cause tubulointerstitial inflammation in mice, which was reversed by inhibition of miR-19b-3p. Clinically, high levels of miR-19b-3p were found in urinary exosomes and correlated with the severity of tubulointerstitial inflammation in patients with diabetic nephropathy.

Conclusion

Exosome/miR-19b-3p/SOCS1 axis played a critical pathologic role in tubulointerstitial inflammation that might represent a new therapeutic target for kidney disease.