Advanced Oxidation Protein Products Induce Hypertrophy and Epithelial-To-Mesenchymal Transition in Human Proximal Tubular Cells through Induction of Endoplasmic Reticulum Stress

Tang, Xun; Rong, Guang; Yang, Baofeng; Zhang, Shaojie; Zhang, Min; Zhang, Jun; Liang, Xiujie

doi:10.1159/000369740

Cited by 28 publications

(22 citation statements)

References 45 publications

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“…Therefore, it is imperative to investigate the mechanisms and explore new effective preventive or therapeutic protocol. DN is characterized by gradual development of renal tubulointerstitial fibrosis, and that the lesion of renal interstitium is a better predictor of progression of kidney damage compared with the glomerular injury [1][2][3]. The balance between the survival and death of renal tubular epithelial cells plays a crucial role in the lesion of renal interstitium [4].…”

Section: Introductionmentioning

confidence: 99%

KIM-1 Mediates High Glucose-Induced Autophagy and Apoptosis in Renal Tubular Epithelial Cells

Gou

Chen

Sheng

et al. 2016

Cell Physiol Biochem

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Background/Aim: To investigate the role of kidney injury molecular 1 (KIM-1) in high glucose-induced autophagy and apoptosis in renal tubular epithelial cells. Methods: Human renal tubular epithelial cells (HK2) were treated with normal glucose (NG, D -glucose 5.6 mmol/L), high glucose (HG, 30 mmol/L), high osmotic (HO, D-glucose 5.6 mmol/L + D-mannitol 24.4 mmol/L), HG + KIM-1 siRNA, HG + siRNA control. The expressions of KIM-1 and microtubule-associated protein 1 light chain 3II (LC3II) were measured by western blot as well as real time PCR; the number of autophagosome was detected by electron microscopy; and the level of apoptosis was analyzed by flow cytometry. Results: In the HG group, the expressions of KIM-1 and LC3II were increased markedly, which was accompanied by more autophagosome and higher level of apoptosis compared with NG group. Silencing of KIM-1 by siRNA inhibited the increases in the levels of LC3II, autophagosome and apoptosis. Conclusion: KIM-1 may mediate high glucose-induced autophagy and apoptosis in renal tubular epithelial cells.

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Section: Introductionmentioning

confidence: 99%

KIM-1 Mediates High Glucose-Induced Autophagy and Apoptosis in Renal Tubular Epithelial Cells

Gou

Chen

Sheng

et al. 2016

Cell Physiol Biochem

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“…and Scr-dependent signaling may play a role (Moon, Kim, Nho, Jang, & Lee, 2014). Both Tang et al (2015) and Pang et al (2016) found that ER stress can induce EMT in HK-2 cells. In this study, we found salubrinal, an inhibitor of ER stress, blocked miR-4756induced EMT, which indicates that miR-4756 regulates HK-2 EMT partly through ER stress.…”

mentioning

confidence: 97%

MiR‐4756 promotes albumin‐induced renal tubular epithelial cell epithelial‐to‐mesenchymal transition and endoplasmic reticulum stress via targeting Sestrin2

Jia

Zheng

Yang

et al. 2018

Journal Cellular Physiology

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Accumulating evidence indicates that proteinuria promotes the progression of diabetic kidney disease (DKD) and induces renal epithelial tubular cell epithelial-to-mesenchymal transition (EMT) and endoplasmic reticulum (ER) stress, but the mechanism remains unclear. In our previous research, we found that miR-4756 levels were increased in the urinary extracellular vesicles of type 2 diabetes mellitus patients with macroalbuminuria. In a preliminary study, we found that miR-4756 may be derived from renal tubular epithelial cells, but its role has not been elucidated. Albumin stimulation significantly increased miR-4756 levels in HK-2 cells. In addition, an miR-4756 mimic accelerated albumin-stimulated HK-2 cell EMT and ER stress, and an miR-4756 inhibitor suppressed these events. We then found that miR-4756 targeted the 3'-untranslated region (UTR) of Sestrin2 and directly suppressed Sestrin2 expression. Furthermore, the induction of EMT and ER stress by the overexpression of miR-4756 was abolished by Sestrin2 overexpression. Moreover, the overexpression of miR-4756 increased ERK1/2 activation and decreased 5' monophosphate-activated protein kinase activation. Thus, our study provides evidence that miR-4756 accelerates the process of DKD through Sestrin2, suggesting that targeting miR-4756 may be a novel strategy for DKD treatment.

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“…TBI initiates a series of complex and dynamic detrimental events, such as hypoxia/ ischemia, excitotoxicity, intracellular calcium overload and elevated intracranial pressure, which establish an environment of mitochondrial dysfunction to favor ROS generation [24,25]. Thus, oxidative stress has long been implicated in the pathophysiology of TBI.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms Underlying H2O2-Evoked Carbonyl Modification of Cytoskeletal Protein and Axon Injury in PC-12 Cells

Zhang

Li²,

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: To investigate the mechanism that enables oxidative stress and cytoskeleton protein carbonylation to contribute to axonal dysfunction in traumatic brain injury (TBI). Methods: We created an in vitro model of neuronal oxidative damage by exposing a neuron-like cell line (PC-12) to different concentrations (100 μM, 200 μM, and 300 μM) of H₂O₂ for 24 h or 48 h. Carbonyl modification of cytoskeletal proteins (β-actin and β-tubulin) and its impact on β-actin/β-tubulin filament dynamics were determined by enzyme-linked immunosorbent assay, immunostaining, and western blotting. Depolymerization of β-actin/β-tubulin filaments was evaluated using the monomer/polymer ratio of each protein via western blotting. Phosphorylation of the neurofilament heavy chain (P-NFH) was used as an axonal injury marker and detected by immunostaining. Results: Our results showed that H₂O₂ treatment led to increased oxidative stress in PC-12 cells, as indicated by the increased generation of malondialdehyde and 8-hydroxydeoxyguanosine and decreased intracellular glutathione levels. H₂O₂ treatment also increased carbonyl modification of total proteins and cytoskeleton proteins β-actin/β-tubulin, which occurred concurrently with the suppression of proteasome activity. Moreover, H₂O₂ treatment increased the generation of the axonal injury marker P-NFH, and depolymerization of the β-actin/β-tubulin filaments was indicated by increased monomer/polymer ratios of each protein. Lastly, overexpression of the proteasome β5 subunit in PC-12 cells significantly reduced the H₂O₂-induced accumulation of carbonylated β-actin/ β-tubulin, P-NFH, and β-actin/β-tubulin depolymerization. Conclusions: We concluded that carbonylation of cytoskeleton proteins could lead to depolymerization of their filaments and axonal injury, and proteasome suppression contributes to the accumulation of carbonylated proteins under oxidative conditions.

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Advanced Oxidation Protein Products Induce Hypertrophy and Epithelial-To-Mesenchymal Transition in Human Proximal Tubular Cells through Induction of Endoplasmic Reticulum Stress

Cited by 28 publications

References 45 publications

KIM-1 Mediates High Glucose-Induced Autophagy and Apoptosis in Renal Tubular Epithelial Cells

KIM-1 Mediates High Glucose-Induced Autophagy and Apoptosis in Renal Tubular Epithelial Cells

MiR‐4756 promotes albumin‐induced renal tubular epithelial cell epithelial‐to‐mesenchymal transition and endoplasmic reticulum stress via targeting Sestrin2

Mechanisms Underlying H2O2-Evoked Carbonyl Modification of Cytoskeletal Protein and Axon Injury in PC-12 Cells

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