Ezrin contributes to impaired podocyte migration and adhesion caused by advanced glycation end products

McRobert, Elizabeth Anne; Bach, Leon Ashley

doi:10.1111/nep.12526

Cited by 6 publications

(5 citation statements)

References 34 publications

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“…Renal tubule epithelial cells play an indispensable part in glomerular filtration barrier [ 5 ]. The structural and functional integrity of renal tubule epithelial cells have close relation with the maintenance of glomerular filtration function [ 6 ]. Dysfunction of renal tubule epithelial cells would result in interstitial fibrosis, glomerulosclerosis as well as proteinuria.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of Salusin-β protects renal tubular epithelial cells against high glucose-induced inflammation, oxidative stress, apoptosis and lipid accumulation via suppressing miR-155-5p

Chen

Jin

2021

Bioengineered

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Diabetic nephropathy (DN) is the main contributor to the excess mortality for patients suffering from diabetes. Here, C57BL/6 mice received 4 weeks of high-fat diet and intraperitoneal injection of STZ (100 mg/kg). Mice with random blood glucose level ≥16.7 mmol/L and positive urine protein were recognized as successful DN model. To construct an in vitro model, HK-2 cells were incubated with 30 mM glucose. RT-qPCR and western blot were employed to measure Salusin-β levels in kidney tissues of DN mice and HG-induced HK-2 cells. Meanwhile, RT-qPCR was performed to detect miR-155-5p level in kidney tissues of DN mice and HG-induced HK-2 cells. TNF-α, IL-6, IL-1β, ROS, SOD and CAT levels were assessed using commercial assay kits. Furthermore, apoptosis of HK-2 cells was assessed via flow cytometric analysis and TUNEL staining. In addition, intracellular lipid accumulation and total cholesterol levels were detected using Oil red O staining and TC ELISA kit. Herein, Salusin-β and miR-155-5p levels were distinctly upregulated in kidney tissues of DN mice and HG-induced HK-2 cells. Downregulation of Salusin-β reduced miR-155-5p expression. Salusin-β silencing dramatically relieved inflammatory and oxidative injury, suppressed apoptosis as well as lipid accumulation induced by HG in HK-2 cells. Besides, miR-155-5p elevation partially abrogated the alleviating effects Salusin-β silencing on HG-induced RTEC injury. In summary, downregulation of Salusin-β protected HK-2 cells against HG-induced inflammation, oxidative stress, apoptosis and ameliorated lipid accumulation through suppressing miR-155-5p, which indicated that Salusin-β could be a potential therapeutic drug for DN.

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Section: Introductionmentioning

confidence: 99%

Downregulation of Salusin-β protects renal tubular epithelial cells against high glucose-induced inflammation, oxidative stress, apoptosis and lipid accumulation via suppressing miR-155-5p

Chen

Jin

2021

Bioengineered

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“…It has been reported that AGEs interact with the N-terminal domain of ezrin and inhibit its actions in proximal tubule cells (60). Notably, a previous study indicated that AGE treatment reduced podocyte adhesion to fibronectin and inhibited migration; however, ezrin overexpression completely reversed the AGE inhibition of podocyte adhesion to fibronectin and partially reversed AGE-induced inhibition of migration (61). This suggests that HG-induced podocyte injury may be mediated by an increased level of AGEs.…”

Section: Discussionmentioning

confidence: 99%

Role of mTOR signaling in the regulation of high glucose‑induced podocyte injury

Zeng

Jiang

et al. 2019

Exp Ther Med

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Podocyte injury, which promotes progressive nephropathy, is considered a key factor in the progression of diabetic nephropathy. The mammalian target of rapamycin (mTOR) signaling cascade controls cell growth, survival and metabolism. The present study investigated the role of mTOR signaling in regulating high glucose (HG)-induced podocyte injury. MTT assay and flow cytometry assay results indicated that HG significantly increased podocyte viability and apoptosis. HG effects on podocytes were suppressed by mTOR complex 1 (mTORC1) inhibitor, rapamycin, and further suppressed by dual mTORC1 and mTORC2 inhibitor, KU0063794, when compared with podocytes that received mannitol treatment. In addition, western blot analysis revealed that the expression levels of Thr-389-phosphorylated p70S6 kinase (p-p70S6K) and phosphorylated Akt (p-Akt) were significantly increased by HG when compared with mannitol treatment. Notably, rapamycin significantly inhibited HG-induced p-p70S6K expression, but did not significantly impact p-Akt expression. However, KU0063794 significantly inhibited the HG-induced p-p70S6K and p-Akt expression levels. Furthermore, the expression of ezrin was significantly reduced by HG when compared with mannitol treatment; however, α-smooth muscle actin (α-SMA) expression was significantly increased. Immunofluorescence analysis on ezrin and α-SMA supported the results of western blot analysis. KU0063794, but not rapamycin, suppressed the effect of HG on the expression levels of ezrin and α-SMA. Thus, it was suggested that the increased activation of mTOR signaling mediated HG-induced podocyte injury. In addition, the present findings suggest that the mTORC1 and mTORC2 signaling pathways may be responsible for the cell viability and apoptosis, and that the mTORC2 pathway could be primarily responsible for the regulation of cytoskeleton-associated proteins.

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“…Ezrin and its phosphorylation site at T567 attracted our attention. Ezrin, a member of the Ezrin–Radixin–Moesin (ERM) protein family, can interact with the cortical actin cytoskeleton and the plasma membrane [46–48]. Ezrin phosphorylation at T567 plays an important role in maintaining cell morphology and specific structure [49, 50], dynamic regulation of B‐cell receptor mobility [51], eight‐cell embryo compaction [52], apoptotic signal transduction [53], etc.…”

Section: Discussionmentioning

confidence: 99%

“…To a great extent, the function of podocytes is based on dynamic regulation of intricate cell structures, especially foot process structures [54]. Ezrin, the actin‐plasma membrane linking protein, is mainly present in the foot processes of podocytes [47, 56], and its phosphorylation at T567 has an essential role in maintaining proper foot process structure [48, 56]. Foot process abnormalities in podocytes and podocyte dysfunction are present in diabetic nephropathy, and a previous study showed that ezrin phosphorylation at T567 was downregulated in the glomeruli of rats with streptozotocin‐induced diabetes [57].…”

Section: Discussionmentioning

confidence: 99%

Label‐free quantitative proteomic and phosphoproteomic analyses of renal biopsy tissues in membranous nephropathy

Luo

Meng

et al. 2021

Proteomics Clinical Apps

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Purpose Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. However, the underlying mechanisms of its occurrence and development are not completely clear. Thus, it is essential to explore the mechanisms. Experimental design Here, we employed label‐free quantification and liquid chromatography‐tandem mass spectrometry analysis techniques to investigate the proteomic and phosphoproteomic alterations in renal biopsy tissues of MN patients. Samples were collected from 16 MN patients and 10 controls. Immunohistochemistry (IHC) was performed to validate the hub phosphoprotein. Results We focused on the changes in the phosphoproteome in MN group versus control group (CG). Totally, 1704 phosphoproteins containing 3241 phosphosites were identified and quantified. The phosphorylation levels of 216 phosphoproteins containing 297 phosphosites were differentially regulated in stage II MN group versus CG, and 333 phosphoproteins containing 461 phosphosites were differentially phosphorylated in stage III MN group versus CG. In each comparison, several differential phosphoproteins were factors, kinases and receptors involved in cellular processes, biological regulation and other biological processes. The subcellular location of most of the differential phosphoproteins was the nucleus. Protein–protein interaction analysis showed that the connections among the differential phosphoproteins were extremely complex, and several signalling pathways probably associated with MN were identified. The hub phosphoprotein was validated by IHC. Conclusions and clinical relevance This investigation can provide direct insight into the global phosphorylation events in MN group versus CG and may help to shed light on the potential pathogenic mechanisms of MN.

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Ezrin contributes to impaired podocyte migration and adhesion caused by advanced glycation end products

Abstract: These results show a role for ezrin in AGE-induced podocyte damage and suggest a new avenue for possible therapeutic intervention in diabetic nephropathy.

Cited by 6 publications

References 34 publications

Downregulation of Salusin-β protects renal tubular epithelial cells against high glucose-induced inflammation, oxidative stress, apoptosis and lipid accumulation via suppressing miR-155-5p

Downregulation of Salusin-β protects renal tubular epithelial cells against high glucose-induced inflammation, oxidative stress, apoptosis and lipid accumulation via suppressing miR-155-5p

Role of mTOR signaling in the regulation of high glucose‑induced podocyte injury

Label‐free quantitative proteomic and phosphoproteomic analyses of renal biopsy tissues in membranous nephropathy

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