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Mesenchymal stem cells alleviate acute kidney injury via miR-107-mediated regulation of ribosomal protein S19.

ABSTRACT: Background:The characteristics of mesenchymal stem cells (MSCs) in the repair of acute kidney injury (AKI) have been extensively studied. However, some potential molecular mechanisms remain indistinct. The aim of this study was to combine published microRNA (miRNA) transcriptional profiling with quantitative proteomic analyses to reveal specific miRNAs or genes for MSC-based therapy in AKI. Methods:Transcriptome data containing significantly changed miRNAs in renal tissue from AKI mice treated with and without MSCs were downloaded. Proteomics resources were downloaded from a human proximal renal tubule cell line (HK-2) that served as a good in vitro model for AKI treated with MSCs. We connected the proteomics data with transcriptional records based on miRNA function. Differentially expressed genes (DEGs) were sorted. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was conducted, and protein-protein interaction (PPI) chains were formed. The genes identified in the analyses were verified in a cisplatin-induced AKI rat model and in HK-2 cells exposed to cisplatin and cocultured with MSCs. Results:A total of 207 specific DEGs were sorted. The ribosomal pathway was identified in pathway enrichment, and ribosomal proteins were identified from the PPI network complex. The targeting of the microRNAs, miR-107 to RPS19, was directly verified by the dual-luciferase method. miR-107 knockdown induced RPS19 expression, protected HK-2 cells from cisplatin-induced apoptosis, and promoted cell proliferation. Conclusions:By analyzing comprehensive bioinformatics data, we have confirmed the DEGs and pathways in AKI treated with MSCs. Bone marrow-derived MSCs reduce miR-107 expression and increase RPS19 expression by repressing the proliferation of cisplatin-induced AKI cells and initiating apoptosis.

SUBMITTER: Sun W

PROVIDER: S-EPMC6990018 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Mesenchymal stem cells alleviate acute kidney injury via miR-107-mediated regulation of ribosomal protein S19.

Sun Weinan W Zhu Qing Q Yan Lei L Shao Fengmin F

Annals of translational medicine 20191201 23

<h4>Background</h4>The characteristics of mesenchymal stem cells (MSCs) in the repair of acute kidney injury (AKI) have been extensively studied. However, some potential molecular mechanisms remain indistinct. The aim of this study was to combine published microRNA (miRNA) transcriptional profiling with quantitative proteomic analyses to reveal specific miRNAs or genes for MSC-based therapy in AKI.<h4>Methods</h4>Transcriptome data containing significantly changed miRNAs in renal tissue from AKI ...[more]

PMID: 32042781

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Project description:The use of mesenchymal stem cells (MSCs) has become a new strategy for treating diabetic kidney disease (DKD). However, the role of placenta derived mesenchymal stem cells (P-MSCs) in DKD remains unclear. This study aims to investigate the therapeutic application and molecular mechanism of P-MSCs on DKD from the perspective of podocyte injury and PINK1/Parkin-mediated mitophagy at the animal, cellular, and molecular levels. Western blotting, reverse transcription polymerase chain reaction, immunofluorescence, and immunohistochemistry were used to detect the expression of podocyte injury-related markers and mitophagy-related markers, SIRT1, PGC-1α, and TFAM. Knockdown, overexpression, and rescue experiments were performed to verify the underlying mechanism of P-MSCs in DKD. Mitochondrial function was detected by flow cytometry. The structure of autophagosomes and mitochondria were observed by electron microscopy. Furthermore, we constructed a streptozotocin-induced DKD rat model and injected P-MSCs into DKD rats. Results showed that as compared with the control group, exposing podocytes to high-glucose conditions aggravated podocyte injury, represented by a decreased expression of Podocin along with increased expression of Desmin, and inhibited PINK1/Parkin-mediated mitophagy, manifested as a decreased expression of Beclin1, the LC3II/LC3I ratio, Parkin, and PINK1 associated with an increased expression of P62. Importantly, these indicators were reversed by P-MSCs. In addition, P-MSCs protected the structure and function of autophagosomes and mitochondria. P-MSCs increased mitochondrial membrane potential and ATP content and decreased the accumulation of reactive oxygen species. Mechanistically, P-MSCs alleviated podocyte injury and mitophagy inhibition by enhancing the expression of the SIRT1-PGC-1α-TFAM pathway. Finally, we injected P-MSCs into streptozotocin-induced DKD rats. The results revealed that the application of P-MSCs largely reversed the markers related to podocyte injury and mitophagy and significantly increased the expression of SIRT1, PGC-1α, and TFAM compared with the DKD group. In conclusion, P-MSCs ameliorated podocyte injury and PINK1/Parkin-mediated mitophagy inhibition in DKD by activating the SIRT1-PGC-1α-TFAM pathway.

Dataset Information

Mesenchymal stem cells alleviate acute kidney injury via miR-107-mediated regulation of ribosomal protein S19.

Publications

Mesenchymal stem cells alleviate acute kidney injury via miR-107-mediated regulation of ribosomal protein S19.

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