Exosomes from high glucose-treated glomerular endothelial cells activate mesangial cells to promote renal fibrosis

Wu, Xiaoming; Gao, Yanbin; Cui, Fang-Qiang; Zhang, Na

doi:10.1242/bio.015990

Cited by 96 publications

(88 citation statements)

References 35 publications

(39 reference statements)

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“…Exosomes are the nanosized membrane-bound delivery vesicles, which play a critical role in regulating cellular biofunction by mediating cell-to-cell communication [31]. Exosomes extracted from HG-treated glomerular endothelial cells (GECs) can be internalized by podocytes, leading to podocyte EMT and renal fibrosis [32,33]. In contrast, some exosomes exert protective effects to be used for treatment of many diseases including podocyte injury and kidney disease.…”

Section: Discussionmentioning

confidence: 99%

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

Jin

Wang

Zhao

et al. 2020

BioMed Research International

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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. Conclusion. 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.

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Section: Discussionmentioning

confidence: 99%

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

Jin

Wang

Zhao

et al. 2020

BioMed Research International

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“…This knowledge may resolve some of these controversies by allowing us to identify the pharmacological concentration and genuine functions of SCFAs in kidney tissue, be it proor anti-inflammatory. GMCs proliferation and hypertrophy, ECM accumulation, as well as consequent renal fibrosis induced by high glucose, AGEs, or LPS have been recognized as major pathogenic events in the progression of renal failure in DN [17]. In this research, the MTT results showed that LPS (1 μg/ml) could induce proliferation of GMCs, however, the pharmacological concentrations of SCFAs (25 mM Ac, 12.5 mM Pr, or 5 mM But) or GPR43 agonist (1 μM) intervention inhibited GMCs proliferation following LPS treatment.…”

Section: Discussionmentioning

confidence: 99%

Short-Chain Fatty Acids Inhibit Oxidative Stress and Inflammation in Mesangial Cells Induced by High Glucose and Lipopolysaccharide

Huang

Guo

Deng

et al. 2017

Exp Clin Endocrinol Diabetes

137

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Recently, an connection between Short-chain fatty acids (SCFAs) produced by intestinal microbiota and kidney has been revealed. The aim of this study was to explore whether SCFAs or their specific G protein-coupled receptors 43 (GPR43) agonist inhibit oxidative stress and inflammatory response in glomerular mesangial cells (GMCs) induced by high glucose and lipopolysaccharide (LPS). Our research showed that treatment with SCFAs, especially acetate and butyrate, or GPR43 agonist significantly inhibited GMCs proliferation induced by high glucose and LPS, and then reversed the production of reactive oxygen species (ROS) and malondialdehyde (MDA) but increased levels of antioxidant enzyme superoxide dismutase (SOD). Furthermore, SCFAs or GPR43 agonist obviously increased the protein expression of GPR43 induced by high glucose and LPS, but diminished the expression of adhesion molecule intercellular adhesion molecule-1 (ICAM-1), and then decreased the proinflammatory cytokine monocyte chemoattractant protein (MCP-1) and interleukin-1β (IL-1β) release from GMCs stimulated by the high glucose and LPS. These combined results support the hypothesis that SCFAs or GPR43 agonist can inhibit oxidative stress and inflammation of GMCs induced by high glucose and LPS, suggesting that SCFAs induced signaling pathway may act as new therapeutic targets of diabetic nephropathy (DN).

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“…These synthesized and secreted cytokines can then bind to the specific receptors on GMC, thus promoting the proliferation and activation of GMC via feedback. Therefore, one enhanced self-regulated GMC activity loop can be formed, and this loop can cause sustained GMC injury and ECM accumulation (21,22). The accumulation and expansion of ECM can cause capillaries to be under pressure and a reduction in their filtration areas, followed by the deterioration of renal function.…”

Section: Discussionmentioning

confidence: 99%

Impacts of the serum containing total flavonoids of Ajuga on rat glomerular mesangial cells

Nan

Huang

Lai

et al. 2017

Molecular Medicine Reports

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The aim of the current study was to investigate the impacts and possible mechanisms of total flavonoids of Ajuga (TFA) on glomerular mesangial cells (GMC) through in vitro observations of the impacts of TFA‑containing serum on GMC proliferation and extracellular matrix (ECM) secretion in lipopolysaccharides (LPS)‑induced rats. Rat GMC was cultured in vitro, using LPS to stimulate the proliferation of GMC and the secretion of ECM; meanwhile, TFA‑containing serum (TFA‑S) was used for the intervention. Methyl thiazolyl tetrazolium (MTT) assay was performed to test the proliferation of GMC; enzyme‑linked immunosorbent assay (ELISA) was used to detect the expressions of fibronectin (FN) and collagen IV (Col‑IV) in cell supernatant, flow cytometry was performed to detect the cell cycle, and reverse transcription-polymerase chain reaction was performed to detect the expression levels of matrix metalloproteinase 9 (MMP‑9) mRNA and transforming growth factor β1 (TGF‑β1) mRNA. The GMC proliferation and the expressions of FN and Col‑IV in cell supernatant were significantly reduced after 24 and 48 h TFA‑S intervention (P<0.05 or 0.01). A total of 48 h subsequent to the intervention, the proportion of GMC in the G1 phase and the relative expression of MMP‑9 mRNA were significantly increased (P<0.05 or 0.01), however the proportion of GMC in S phase and the relative expression of TGF‑β1 mRNA were significantly reduced (P<0.05 or 0.01). TFA‑S can inhibit LPS‑induced GMC proliferation and ECM accumulation, and its roles are associated with regulating the cell cycle and the expression levels of TGF‑β1 and MMP‑9.

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Exosomes from high glucose-treated glomerular endothelial cells activate mesangial cells to promote renal fibrosis

Cited by 96 publications

References 35 publications

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

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

Short-Chain Fatty Acids Inhibit Oxidative Stress and Inflammation in Mesangial Cells Induced by High Glucose and Lipopolysaccharide

Impacts of the serum containing total flavonoids of Ajuga on rat glomerular mesangial cells

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