Exosomal miRNA-215-5p Derived from Adipose-Derived Stem Cells Attenuates Epithelial-Mesenchymal Transition of Podocytes by Inhibiting ZEB2. 2020

Juan Jin, and Yunguang Wang, and Li Zhao, and Wenli Zou, and Mingming Tan, and Qiang He
Department of Nephrology, Zhejiang Provincial People's Hospital, Zhejiang 310014, China.

BACKGROUND Podocyte migration is actively involved in the process of podocyte loss and proteinuria production, which is closely associated with the development of diabetic nephropathy (DN). Exosomes from adipose-derived stem cells (ADSCs-Exos) effectively inhibit podocyte apoptosis in the treatment of DN. However, how ADSCs-Exos affect the migration of podocytes is obscure. This study is aimed at exploring the regulatory role of ADSCs-Exos on cell migration and the underlying mechanism. METHODS ADSCs-Exo was authenticated by transmission electron microscopy (TEM), western blotting, and flow cytometry. Cell viability and migration ability of podocytes were measured by CCK8 and Transwell assays, respectively. Relative expressions of miRNAs and mRNAs were determined by qRT-PCR. The transmitting between PKH26-labeled exosome and podocytes was evaluated by IF assay. Dual luciferase reporter assay was employed to detect the relationship between miR-215-5p and ZEB2. RESULTS The exposure to serum from DN patient (hDN-serum) significantly inhibited cell viability of podocytes, but ADSCs-Exo addition notably blunts cytotoxicity induced by the transient stimulus of hDN-serum. Besides, ADSCs-Exo administration powerfully impeded high glucose- (HG-) induced migration and injury of podocyte. With the podocyte dysfunction, several miRNAs presented a significant decline under the treatment of HG including miR-251-5p, miR-879-5p, miR-3066-5p, and miR-7a-5p, all of which were rescued by the addition of ADSCs-Exo. However, only miR-251-5p was a key determinant in the process of ADSCs-Exo-mediated protective role on podocyte damage. The miR-251-5p inhibitor counteracted the improvement from the ADSCs-Exo preparation on HG-induced proliferation inhibition and migration promotion. Additionally, miR-215-5p mimics alone remarkably reversed HG-induced EMT process of podocyte. Mechanistically, we confirmed that ADSCs-Exos mediated the shuttling of miR-215-5p to podocyte, thereby protecting against HG-induced metastasis, possibly through inhibiting the transcription of ZEB2. CONCLUSIONS ADSCs-Exo has the protective effect on HG-evoked EMT progression of podocytes thru a mechanism involving ZEB2. Potentially, the ADSCs-Exo preparation is a useful therapeutic strategy for improving podocyte dysfunction and DN symptoms clinically.

UI MeSH Term Description Entries
D008297 Male Males
D008810 Mice, Inbred C57BL One of the first INBRED MOUSE STRAINS to be sequenced. This strain is commonly used as genetic background for transgenic mouse models. Refractory to many tumors, this strain is also preferred model for studying role of genetic variations in development of diseases. Mice, C57BL,Mouse, C57BL,Mouse, Inbred C57BL,C57BL Mice,C57BL Mice, Inbred,C57BL Mouse,C57BL Mouse, Inbred,Inbred C57BL Mice,Inbred C57BL Mouse
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D002470 Cell Survival The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. Cell Viability,Cell Viabilities,Survival, Cell,Viabilities, Cell,Viability, Cell
D000074165 Zinc Finger E-box Binding Homeobox 2 A transcription factor that consists of 8 CYS2-HIS2 ZINC FINGERS flanking a central HOMEOBOX. It binds to the 5'-CACCT-3' DNA sequence located within E-BOX ELEMENTS of many genes essential for embryonic growth and development and regulates their activity; it represses transcription of the E-CADHERIN gene. Mutations in the ZEB2 gene are associated with MOWAT-WILSON SYNDROME. Smad-Interacting Protein 1,Zeb2 Transcription Factor,Zinc Finger E-box Binding Homeobox 2 Protein,Smad Interacting Protein 1,Transcription Factor, Zeb2,Zinc Finger E box Binding Homeobox 2,Zinc Finger E box Binding Homeobox 2 Protein
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D050199 Podocytes Highly differentiated epithelial cells of the visceral layer of BOWMAN CAPSULE of the KIDNEY. They are composed of a cell body with major CELL SURFACE EXTENSIONS and secondary fingerlike extensions called pedicels. They enwrap the KIDNEY GLOMERULUS capillaries with their cell surface extensions forming a filtration structure. The pedicels of neighboring podocytes interdigitate with each other leaving between them filtration slits that are bridged by an extracellular structure impermeable to large macromolecules called the slit diaphragm, and provide the last barrier to protein loss in the KIDNEY. Visceral Epithelial Cells, Glomerular,Epithelial Cells, Glomerular Visceral,Glomerular Visceral Epithelial Cells,Podocyte
D055354 Exosomes A type of extracellular vesicle, containing RNA and proteins, that is secreted into the extracellular space by EXOCYTOSIS when MULTIVESICULAR BODIES fuse with the PLASMA MEMBRANE.
D058750 Epithelial-Mesenchymal Transition Phenotypic changes of EPITHELIAL CELLS to MESENCHYME type, which increase cell mobility critical in many developmental processes such as NEURAL TUBE development. NEOPLASM METASTASIS and DISEASE PROGRESSION may also induce this transition. Epithelial-Mesenchymal Transformation,Epithelial Mesenchymal Transformation,Epithelial Mesenchymal Transition,Transformation, Epithelial-Mesenchymal,Transition, Epithelial-Mesenchymal
D059630 Mesenchymal Stem Cells Mesenchymal stem cells, also referred to as multipotent stromal cells or mesenchymal stromal cells are multipotent, non-hematopoietic adult stem cells that are present in multiple tissues, including BONE MARROW; ADIPOSE TISSUE; and WHARTON JELLY. Mesenchymal stem cells can differentiate into mesodermal lineages, such as adipocytic, osteocytic and chondrocytic. Adipose Tissue-Derived Mesenchymal Stem Cell,Adipose Tissue-Derived Mesenchymal Stromal Cell,Adipose-Derived Mesenchymal Stem Cell,Bone Marrow Mesenchymal Stem Cell,Mesenchymal Stromal Cell,Mesenchymal Stromal Cells,Multipotent Bone Marrow Stromal Cell,Multipotent Mesenchymal Stromal Cell,Adipose Tissue-Derived Mesenchymal Stem Cells,Adipose Tissue-Derived Mesenchymal Stromal Cells,Adipose-Derived Mesenchymal Stem Cells,Adipose-Derived Mesenchymal Stromal Cells,Bone Marrow Mesenchymal Stem Cells,Bone Marrow Stromal Cell,Bone Marrow Stromal Cells,Bone Marrow Stromal Cells, Multipotent,Bone Marrow Stromal Stem Cells,Mesenchymal Progenitor Cell,Mesenchymal Progenitor Cells,Mesenchymal Stem Cell,Mesenchymal Stem Cells, Adipose-Derived,Mesenchymal Stromal Cells, Multipotent,Multipotent Bone Marrow Stromal Cells,Multipotent Mesenchymal Stromal Cells,Stem Cells, Mesenchymal,Wharton Jelly Cells,Wharton's Jelly Cells,Adipose Derived Mesenchymal Stem Cell,Adipose Derived Mesenchymal Stem Cells,Adipose Derived Mesenchymal Stromal Cells,Adipose Tissue Derived Mesenchymal Stem Cell,Adipose Tissue Derived Mesenchymal Stem Cells,Adipose Tissue Derived Mesenchymal Stromal Cell,Adipose Tissue Derived Mesenchymal Stromal Cells,Mesenchymal Stem Cells, Adipose Derived,Progenitor Cell, Mesenchymal,Progenitor Cells, Mesenchymal,Stem Cell, Mesenchymal,Stromal Cell, Mesenchymal,Stromal Cells, Mesenchymal,Wharton's Jelly Cell,Whartons Jelly Cells

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