High Glucose Induces Mesangial Cell Apoptosis through miR-15b-5p and Promotes Diabetic Nephropathy by Extracellular Vesicle Delivery

Tsai, Yi‐Chun; Kuo, Mei‐Chuan; Hung, Wei‐Wen; Wu, Lu; Wu, Ping-Hsun; Chang, Wei‐An; Kuo, Po‐Lin; Hsu, Ya‐Ling

doi:10.1016/j.ymthe.2020.01.014

Cited by 52 publications

(33 citation statements)

References 29 publications

(39 reference statements)

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“…In our prophase research, we nd that functional alterations in GMCs in response to high extracellular glucose levels have been involved in the pathophysiology of DN (Ni WJ et al, 2016;Qiu YY et al, 2017). The increased intracellular glucose concertation results in activation of several pathophysiologic mechanisms, including the metabolic polyol pathway, increased synthesis of TGF-β1, intracellular production of advanced glycation end products, and the generation of reactive oxygen species (Tsai YC et al, 2020). All of these effects contribute to the increased synthesis of the mesangial matrix, brogenesis components such as bronectin and collagen, leading to mesangial expansion and glomerular sclerosis.…”

Section: Discussionmentioning

confidence: 94%

“…DN is an ordinary complication of diabetes mellitus which is the leading cause of end-stage renal disorder, posting a menacing threat to public health, due to it caused multiple pathological changes (Tervaert TW et al, 2010). Among these alterations, HG-induced proliferation and ECM deposition of the mesangial cell have been identi ed as the prominent pathological features in the progression of DN (Xie R et al, 2017;Tsai YC et al, 2020). It is worth noting that GMCs abnormal proliferation may be present in DN patients before the onset of clinical manifestations (Turgut F et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

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Berberine Interferes With the Abnormal Glomerular Mesangial Cell C Ycle Re-Distribution to Alleviate Diabetic Nephropathy via PI3K/AKT/AS160/GLUT4 Signaling Pathway

Guan

Zeng

et al. 2021

Preprint

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Background: Berberine plays a critical role of the glomerular mesangial cells (GMCs) abnormal proliferation during diabetic nephropathy (DN). This study aims to explore the intervention effect of BBR on DN mice and investigate the potential mechanism targeting abnormal GMCs proliferation. Methods: Streptozotocin-induced mice were used to determine the effect of BBR on the renal injury. In vitro, GMCs are cultured in high glucose (30 mmol/L). EdU and MTT assay are used for screening the optimum BBR concentration and intervention time. Flow cytometry is applied to analyze the cell cycle re-distribution. Western blot and RT-qPCR are devoted to studying the relative expression of molecules in PI3K/AKT/AS160/GLUT4 signaling pathway. Additionally, 2-NBDG assay is selected for measuring the glucose uptake of GMCs. Results: HE and PAS staining revealed that the notable mesangial matrix expansion, glomerular hypertrophy and glycogen deposition in diabetic kidney can be alleviated after BBR treatment. Moreover, BBR significantly reduced the positive expression of GLUT4 in tubulointerstitium and glomerular region. EdU shows that high glucose induces the abnormal proliferation of GMCs, which becomes more apparently as time goes on (20h→28h). Meantime, BBR (60 and 90 μmol/L) can not only increase the proportion of G1 phase, but also reduce the proportion of S phase. After 24 h, the same sort of phenomenon has cropped up in BBR (30 μmol/L) group. BBR (60 μmol/L)) significantly degraded the levels of PI3K-p85, p-AKT, p-AS160, and the membrane-GLUT4, while indistinguishable changes of their total protein expressions. Additionally, BBR prominently reduced the glucose uptake and retard the cell cycle of GMCs to stay at G1 phase. Conclusions: The rearrangement effect of BBR on cell cycle is related with PI3K/AKT signaling pathway and GLUT4 trafficking. The key findings of our study collectively indicate that the treatment of GMCs proliferation can be a novel therapeutic strategy in DN.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Berberine Interferes With the Abnormal Glomerular Mesangial Cell C Ycle Re-Distribution to Alleviate Diabetic Nephropathy via PI3K/AKT/AS160/GLUT4 Signaling Pathway

Guan

Zeng

et al. 2021

Preprint

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“…These factors individually and/or synergistically result in the pathological features of DN, including the thickening of the glomerular basement membrane, damage to glomerular cells, mesangial matrix expansion and tubulointerstitial fibrosis (30). HG-induced damage to glomerular cells, including glomerular endothelial cells, podocytes and mesangial cells, is a key factor in exacerbating the progression of DN (11,(30)(31)(32). Moreover, damage to glomerular endothelial cells and podocytes causes filtration barrier damage and accelerates the excretion of albuminuria (7,31).…”

Section: Discussionmentioning

confidence: 99%

“…Mesangial cell injury, characterized by an increase in apoptosis, excessive inflammatory cytokine production and extracellular matrix synthesis, is a basic pathological change of DN (7,9). Clinical, animal and in vitro studies have revealed that HG can induce mesangial cell apoptosis, which aggravates the pathological process of DN (10,11). The hyperglycemia-induced excessive generation of reactive oxygen species (ROS) has been recognized as one of the causes for DN (10)(11)(12); however, the precise mechanisms involved are yet to be fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

Piperazine ferulate attenuates high glucose‑induced mesangial cell injury via the regulation of p66^Shc

et al. 2021

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Diabetic nephropathy (DN) is a severe microvascular complication of diabetes. Hyperglycemia-induced glomerular mesangial cells injury is associated with microvascular damage, which is an important step in the development of DN. Piperazine ferulate (PF) has been reported to exert protective effects against the progression of DN. However, whether PF prevents high glucose (HG)-induced mesangial cell injury remains unknown. The aim of the present study was to investigate the effects of PF on HG-induced mesangial cell injury and to elucidate the underlying mechanisms. Protein and mRNA expression levels were determined via western blot analysis and reverse transcription-quantitative PCR, respectively. IL-6 and TNF-α levels were measured using ELISA. Reactive oxygen species levels and NF-κB p65 nuclear translation were determined via immunofluorescence analysis. Apoptosis was assessed by measuring lactate dehydrogenase (LDH) release, as well as using MTT and flow cytometric assays. The mitochondrial membrane potential of mesangial cells was determined using the JC-1 kit. The results revealed that LDH release were increased; however, cell viability and mitochondrial membrane potential were decreased in the HG group compared with the control group. These changes were inhibited after the mesangial cells were treated with PF. Moreover, PF significantly inhibited the HG-induced production of inflammatory cytokines and the activation of NF-κB in mesangial cells. PF also attenuated the HG-induced upregulation of the expression levels of fibronectin and collagen 4A1. Furthermore, the overexpression of p66 Src homology/collagen (Shc) abolished the protective effect of PF on HG-induced mesangial cell injury. In vivo experiments revealed that PF inhibited the activation of inflammatory signaling pathways, glomerular cell apoptosis and mesangial matrix expansion in diabetic mice. Collectively, the present findings demonstrated that PF attenuated HG-induced mesangial cells injury by inhibiting p66 Shc .

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“…A recent study by Zhang et al (40) found that platelet microparticles with the increased expression of CXCL7, which activated the mTORC1 pathway, mediated glomerular endothelial injury in rats with streptozotocin-induced diabetes and early DN. The uEVs of patients with type 2 diabetes expressed high levels of miR-15b-5p, leading to the apoptosis of mouse mesangial cells through decreasing the translation of Bcl-2 (41). Hence, miR-15-5p promoted DN.…”

Section: Ev-mediated Intranephron Cell-cell Cross-talk and Signaling mentioning

confidence: 99%

Diabetic Nephropathy: Perspective on Extracellular Vesicles

Feng

et al. 2020

Front. Immunol.

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Diabetic nephropathy (DN) is a major microvascular complication of diabetes mellitus. It is the most frequent cause of end-stage renal disease with no definitive therapy available so far. Extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, are nano-and micron-sized heterogeneous vesicles that can be secreted by almost all cell types. Importantly, EVs contain many biologically active materials, such as RNAs, DNAs, proteins, and lipids, from their parental cells, which can be transported to their recipient cells to mediate intercellular communication and signaling. Accumulating studies demonstrated that EVs, mainly exosomes and microvesicles, participated in the pathophysiological process of DN. Recently emerging studies also found that the contents of EVs in the urine (miRNAs, mRNAs, and proteins) could be used as potential biomarkers for DN. Therefore, in this mini-review, the generation, isolation methods, and biological function of EVs were introduced, and then the current information about the mechanism and the diagnostic value in the development of DN was summarized. Moreover, the review also discussed the future challenges of exploring the role of EVs in kidney disease.

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High Glucose Induces Mesangial Cell Apoptosis through miR-15b-5p and Promotes Diabetic Nephropathy by Extracellular Vesicle Delivery

Cited by 52 publications

References 29 publications

Berberine Interferes With the Abnormal Glomerular Mesangial Cell C Ycle Re-Distribution to Alleviate Diabetic Nephropathy via PI3K/AKT/AS160/GLUT4 Signaling Pathway

Berberine Interferes With the Abnormal Glomerular Mesangial Cell C Ycle Re-Distribution to Alleviate Diabetic Nephropathy via PI3K/AKT/AS160/GLUT4 Signaling Pathway

Piperazine ferulate attenuates high glucose‑induced mesangial cell injury via the regulation of p66^Shc

Diabetic Nephropathy: Perspective on Extracellular Vesicles

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High Glucose Induces Mesangial Cell Apoptosis through miR-15b-5p and Promotes Diabetic Nephropathy by Extracellular Vesicle Delivery

Cited by 52 publications

References 29 publications

Berberine Interferes With the Abnormal Glomerular Mesangial Cell C Ycle Re-Distribution to Alleviate Diabetic Nephropathy via PI3K/AKT/AS160/GLUT4 Signaling Pathway

Berberine Interferes With the Abnormal Glomerular Mesangial Cell C Ycle Re-Distribution to Alleviate Diabetic Nephropathy via PI3K/AKT/AS160/GLUT4 Signaling Pathway

Piperazine ferulate attenuates high glucose‑induced mesangial cell injury via the regulation of p66Shc

Diabetic Nephropathy: Perspective on Extracellular Vesicles

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Product

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Piperazine ferulate attenuates high glucose‑induced mesangial cell injury via the regulation of p66^Shc