Human umbilical cord mesenchymal stem cells attenuate podocyte injury under high glucose via TLR2 and TLR4 signaling

Wang, Yinghui; Liu, Jiaxi; Zhang, Qingqing; Wang, Weiwei; Liu, Qingzhen; Liu, Shanshan; Song, Yan; Wang, Xueling; Zhang, Yaping; Li, Shan; Yang, Xue; Lv, Shunzeng; Liu, Gang

doi:10.1016/j.diabres.2021.108702

Cited by 16 publications

(11 citation statements)

References 47 publications

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“…We further performed dual-luciferase reporter gene assay to validate their interplay. Accumulating evidences suggested that TLR4 is upregulated in DN [ 37 ] and is highly expressed in HG-stimulated podocytes [ 30 ] and HK-2 cells [ 38 ]. Liu et al [ 39 ] demonstrated that knockdown of TLR4 attenuated the HG-stimulated podocyte cell apoptosis and reduced cell viability and inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Inflammation may play a crucial role in the pathophysiology of DN, as evidence is mounting [23][24][25]. Hyperglycemia can stimulate the secretion of inflammatory cytokines, induce apoptosis, and generate numerous reactive oxygen species, resulting in injury to renal tubular epithelial cells [26], renal [27], mesangial cells [28,29], and podocytes [30].…”

Section: Discussionmentioning

confidence: 99%

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lncRNA MALAT1 Promotes Diabetic Nephropathy Progression via miR-15b-5p/TLR4 Signaling Axis

Yang

Song

Wang

et al. 2022

Journal of Immunology Research

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Objective. The long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) are closely associated with the pathogenesis of diabetic nephropathy (DN). But a complete mechanism for MALAT1 in DN has yet to be identified. This study investigated the effect of MALAT1 on DN through the regulation of miR-15b-5p/TLR4 signaling. Method. Renal tissues were collected from DN patients. Human renal tubular epithelial cells (HK-2) were used as a model of DN induced by high glucose (HG). We then measured the viability, apoptosis, and inflammatory cytokine levels of HK-2 cells using the corresponding assays. Following transfections of si-MALAT1, si-MALAT1+miR-15b-5p inhibitor, or si-MALAT1+vector TLR4 into HG-stimulated HK-2 cells, cell viability, apoptosis, and inflammatory cytokines were again measured. Furthermore, dual-luciferase reporter assay validated the interactions of MALAT1/miR-15b-5p and miR-15b-5p/TLR4. In addition, the interaction between MALAT1 and miR-15b-5p was investigated by RNA immunoprecipitation (RIP). Results. A significant upregulation of MALAT1 was observed in DN kidney tissues, as well as in HG-stimulated HK-2 cells. MALAT1 knockdown attenuates the inhibition of cell viability, apoptosis, and inflammatory response induced by HG in HK-2 cells. Moreover, a miR-15b-5p inhibitor or TLR4 overexpression reversed the above effects induced by MALAT1 knockdown. Conclusion. These results indicate that reduced MALAT1 ameliorates HG-stimulated HK-2 cell damage through an inhibition of the miR-15b-5p/TLR4 axis. MALAT1 may serve as a biomarker and potential therapeutic target for DN.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

lncRNA MALAT1 Promotes Diabetic Nephropathy Progression via miR-15b-5p/TLR4 Signaling Axis

Yang

Song

Wang

et al. 2022

Journal of Immunology Research

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“…Finally, SCs from UCB can improve glycemic control and alleviate glomerular hypertrophy in type 2 DM [ 160 ] and this renoprotective effect was confirmed in more recent studies [ 161 , 162 ]. Human UC-MSCs counteract hyperglycemia-activated TLR 2 and 4 signaling pathways and pro-inflammatory cytokines in podocytes in DN [ 150 ].…”

Section: Stem Cells and Extracellular Vesicles As Therapeutic Tools F...mentioning

confidence: 99%

Extracellular Vesicles Released from Stem Cells as a New Therapeutic Strategy for Primary and Secondary Glomerulonephritis

Quaglia

Merlotti

Fornara

et al. 2022

IJMS

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Current treatment of primary and secondary glomerulopathies is hampered by many limits and a significant proportion of these disorders still evolves towards end-stage renal disease. A possible answer to this unmet challenge could be represented by therapies with stem cells, which include a variety of progenitor cell types derived from embryonic or adult tissues. Stem cell self-renewal and multi-lineage differentiation ability explain their potential to protect and regenerate injured cells, including kidney tubular cells, podocytes and endothelial cells. In addition, a broad spectrum of anti-inflammatory and immunomodulatory actions appears to interfere with the pathogenic mechanisms of glomerulonephritis. Of note, mesenchymal stromal cells have been particularly investigated as therapy for Lupus Nephritis and Diabetic Nephropathy, whereas initial evidence suggest their beneficial effects in primary glomerulopathies such as IgA nephritis. Extracellular vesicles mediate a complex intercellular communication network, shuttling proteins, nucleic acids and other bioactive molecules from origin to target cells to modulate their functions. Stem cell-derived extracellular vesicles recapitulate beneficial cytoprotective, reparative and immunomodulatory properties of parental cells and are increasingly recognized as a cell-free alternative to stem cell-based therapies for different diseases including glomerulonephritis, also considering the low risk for potential adverse effects such as maldifferentiation and tumorigenesis. We herein summarize the renoprotective potential of therapies with stem cells and extracellular vesicles derived from progenitor cells in glomerulonephritis, with a focus on their different mechanisms of actions. Technological progress and growing knowledge are paving the way for wider clinical application of regenerative medicine to primary and secondary glomerulonephritis: this multi-level, pleiotropic therapy may open new scenarios overcoming the limits and side effects of traditional treatments, although the promising results of experimental models need to be confirmed in the clinical setting.

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“…6 Mounting evidence substantiates the therapeutic efficiency of HUC-MSCs in alleviating symptoms of DKD and other kidney diseases. [7][8][9] Exosomal-based paracrine regulation has been established to play an important role in the mechanisms underlying the efficacy of MSC therapy. Indeed, exosomes are nanosized extracellular vesicles (EVs) that play a critical role in transporting bio-messages in cell-to-cell communication, containing small molecule proteins, lipids, mRNAs, and miRNAs.…”

Section: Introductionmentioning

confidence: 99%

“…Current evidence suggests that the human umbilical cord (HUC) is an ideal source of MSCs for clinical application due to its low immunogenicity 6 . Mounting evidence substantiates the therapeutic efficiency of HUC‐MSCs in alleviating symptoms of DKD and other kidney diseases 7–9 . Exosomal‐based paracrine regulation has been established to play an important role in the mechanisms underlying the efficacy of MSC therapy.…”

Section: Introductionmentioning

confidence: 99%

Exosomes derived from mesenchymal stem cells attenuate diabetic kidney disease by inhibiting cell apoptosis and epithelial‐to‐mesenchymal transition via miR‐424‐5p

et al. 2022

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Diabetic kidney disease (DKD) is well-acknowledged as one of the most common complications in diabetes mellitus. Recent studies have demonstrated the promising role of mesenchymal stem cell-derived exosomes (MSC-exos) as a cell-free treatment strategy for DKD. The present study sought to investigate the therapeutic potential and the underlying mechanisms of MSC-exos in DKD. The authentication of MSC-exos was validated by western blot, transmission electron microscope (TEM), and nanosight tracking analysis (NTA). Apoptosis was detected by western blot, TUNEL staining, and flow cytometry. Epithelialto-mesenchymal transition (EMT) was evaluated by western blot and immunofluorescence. The relationship between miR-424-5p and Yes-associated protein 1 (YAP1) was revealed by dual luciferase reporter assay. We observed that MSCexos could attenuate DKD by decreasing cell apoptosis and inhibiting epithelialto-mesenchymal transition (EMT) in diabetic kidneys in db/db mice. Besides, we documented that MSC-exos could reverse high glucose-induced apoptosis and EMT in HK2 cells. Interestingly, miR-424-5p derived from MSC-exos could inhibit YAP1 activation in HK2 cells, resulting in alleviation of high glucose-induced cell apoptosis and EMT. Our study provides novel insights into MSC-exos-mediated protective effect in DKD. MSC-exos could inhibit high glucose-induced apoptosis and EMT through miR-424-5p targeting of YAP1.

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Human umbilical cord mesenchymal stem cells attenuate podocyte injury under high glucose via TLR2 and TLR4 signaling

Cited by 16 publications

References 47 publications

lncRNA MALAT1 Promotes Diabetic Nephropathy Progression via miR-15b-5p/TLR4 Signaling Axis

lncRNA MALAT1 Promotes Diabetic Nephropathy Progression via miR-15b-5p/TLR4 Signaling Axis

Extracellular Vesicles Released from Stem Cells as a New Therapeutic Strategy for Primary and Secondary Glomerulonephritis

Exosomes derived from mesenchymal stem cells attenuate diabetic kidney disease by inhibiting cell apoptosis and epithelial‐to‐mesenchymal transition via miR‐424‐5p

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