Oxidative Stress and Cell Senescence Combine to Cause Maximal Renal Tubular Epithelial Cell Dysfunction and Loss in an in vitro Model of Kidney Disease

Small, David M.; Bennett, Nigel C.; Roy, Sandrine; Gabrielli, Brian; Johnson, David W.; Gobé, Glenda C.

doi:10.1159/000350726

Cited by 55 publications

(41 citation statements)

References 60 publications

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“…CKD is characterized by a continuous reduction in structural and functional decline in the kidney function that involves increased inflammation and oxidative stress, and reduced antioxidant capacity (Small et al, 2012b). The objective of this study was to assess the were injured with oxidative stress and then increased with use of the extracts, and we believe this also helps mediate cell survival in this model (Sanchez-Capelo, 2005), but the pro-fibrotic role of…”

Section: Discussionmentioning

confidence: 99%

“…Oxidative stress inducedapoptosis is well-documented and manifests in renal pathologies as kidney atrophy and reduced kidney function (Small et al, 2012b). and inhibited Bcl-X L in kidney cells (Cuttle et al, 2001;Gao et al, 2012) and cancer (HeLa) cells (Singh et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Oxidative stress is a result of perturbations in normal oxidant signalling networks, primarily regulated by reactive oxygen species (ROS) and endogenous antioxidants (Small et al, 2012b). Kidney proximal tubular epithelial cells contain large numbers of mitochondria and are the most reliant upon oxidative phosphorylation and most susceptible to ROS-induced injury of cells of the kidney nephron (Agarwal, 2003).…”

Section: Introductionmentioning

confidence: 99%

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Protection against oxidative stress-induced apoptosis in kidney epithelium by Angelica and Astragalus

Shahzad

Small

Morais

et al. 2016

Journal of Ethnopharmacology

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Ethnopharmacological relevance: Astragalus membranaceus either alone or in combination withAngelica sinensis has been used traditionally for kidney disease in East Asia and China for thousands of years. Previous studies using in vivo animal models have shown the benefits of these medicinal herbs in kidney diseases that involve oxidative stress. However, the mechanisms by which these medicinal herbs protect kidney cells remain largely unknown.Aim of the study: To investigate the mechanisms by which ethanol, methanol and aqueous crude extracts of roots of A. membranaceus and A. sinensis afford protection to human kidney proximal tubular epithelial cells, using an in vitro model of oxidative stress. Materials and Methods:Ethanol, methanol and aqueous extracts of roots of A. membranaceus and A. sinensis were prepared by a three-solvent sequential process. HK2 human kidney proximal tubular epithelial cells were treated with H 2 O 2 alone (0.5 mM) or in combination with different concentrations of extracts. Cell mitosis and death (microscopy) and cell viability (MTT assay) were compared. Western immunoblot was used to study expression of apoptosis-related proteins (pro-apoptotic Bax andanti-apoptotic Bcl-X L ), and cell survival (NFκB subunits p65 and p50), pro-inflammatory (TNF-α) and protective (TGFβ1) proteins.Results: H 2 O 2 -induced oxidative stress significantly increased apoptosis and reduced cell survival; upregulated pro-apoptotic and down-regulated Bcl-X L ; increased NFκB (p65, p50); increased TNFα; and decreased TGFβ1. All changes indicated kidney damage and dysfunction.All were modulated by all extracts of both plant species, except for NFκB which was only modulated by extracts of A. membranaceus. Conclusions:In conclusion, in a model of oxidative stress that might occur after nephrotoxicity, the plant extracts were protective via anti-apoptotic and anti-inflammatory mechanisms.3

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Protection against oxidative stress-induced apoptosis in kidney epithelium by Angelica and Astragalus

Shahzad

Small

Morais

et al. 2016

Journal of Ethnopharmacology

Self Cite

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“…Previous study showed that cell senescence induces renal tubular epithelial cell dysfunction and loss in the model of renal disease. 47) It is also reported that cell senescence could contribute to organ aging and the expression of senescence-associated genes are enhanced in aging kidney. 48) These results provide evidence towards the effect of ROS and cell senescence in renal damage, as we show in Fig.…”

Section: Hfd and Hg Culture Comparisonmentioning

confidence: 99%

Resveratrol Protects against High-Fat Diet Induced Renal Pathological Damage and Cell Senescence by Activating SIRT1

Zhang

et al. 2016

Biological & Pharmaceutical Bulletin

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Obesity-related renal diseases have been a worldwide issue. Effective strategy that prevents high fat-diet induced renal damage is of great significance. Resveratrol, a natural plant polyphenol, is famous for its antioxidant activity, cardioprotective effects and anticancer properties. However whether resveratrol can play a role in the treatment of renal diseases is unknown. In this study, we added resveratrol in normal glucose or high glucose medium and provide evidences that resveratrol protects against high-glucose triggered oxidative stress and cell senescence. Moreover, mice were fed with standard diet, standard diet plus resveratrol, high-fat diet or high-fat diet plus resveratrol for 3 months, and results show that resveratrol treatment prevents high-fat diet induced renal pathological damage by activating SIRT1, a key member in the mammalian sirtuin family that response to calorie restriction life-extension method. This research confirms the potential role of resveratrol in the treatment of renal diseases and may provide an effective and convenient method to mimic the beneficial effects of calorie restriction.

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“…Most of all, pediatric nephrolithiasis presents increasing morbidity for the past several decades, meanwhile, a concomitant alarming rise in health care costs and burden to the children population suffering this disease [26]. Increasing evidence shows that the ERK signaling pathway and RTEC dysfunction and attrition are central to the pathogenesis of kidney diseases [9,27]. MUC4 is reported as an activator of ERK signaling pathway in epithelial cells [28].…”

Section: Discussionmentioning

confidence: 99%

Mucin 4 Gene Silencing Reduces Oxidative Stress and Calcium Oxalate Crystal Formation in Renal Tubular Epithelial Cells Through the Extracellular Signal-Regulated Kinase Signaling Pathway in Nephrolithiasis Rat Model

Sun¹,

Zou²,

Wang³

et al. 2018

Kidney Blood Press Res

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Background/Aims: Nephrolithiasis plagues a great number of patients all over the world. Increasing evidence shows that the extracellular signal-regulated kinase (ERK) signaling pathway and renal tubular epithelial cell (RTEC) dysfunction and attrition are central to the pathogenesis of kidney diseases. Mucin 4 (MUC4) is reported as an activator of ERK signaling pathway in epithelial cells. In this study, using rat models of calcium oxalate (CaOx) nephrolithiasis, the present study aims to define the roles of MUC4 and ERK signaling pathway as contributors to oxidative stress and CaOx crystal formation in RTEC. Methods: Data sets of nephrolithiasis were searched using GEO database and a heat flow map was drawn. Then MUC4 function was predicted. Wistar rats were prepared for the purpose of model establishment of ethylene glycol and ammonium chloride induced CaOx nephrolithiasis. In order to assess the detailed regulatory mechanism of MUC4 silencing on the ERK signaling pathway and RTEC, we used recombinant plasmid to downregulate MUC4 expression in Wistar rat-based models. Samples from rat urine, serum and kidney tissues were reviewed to identify oxalic acid and calcium contents, BUN, Cr, Ca²⁺ and P³⁺ levels, calcium crystal formation in renal tubules and MUC4 positive expression rate. Finally, RT-qPCR, Western blot analysis, and ELISA were employed to access oxidative stress state and CaOx crystal formation in RTEC. Results: Initially, MUC4 was found to have an influence on the process of nephrolithiasis. MUC4 was upregulated in the CaOx nephrolithiasis model rats. We proved that the silencing of MUC4 triggered the inactivation of ERK signaling pathway. Following the silencing of MUC4 or the inhibition of ERK signaling pathway, the oxalic acid and calcium contents in rat urine, BUN, Cr, Ca²⁺ and P³⁺ levels in rat serum, p-ERK1/2, MCP-1 and OPN expressions in RTEC and H₂O₂ and MDA levels in the cultured supernatant were downregulated, but the GSH-Px, CAT and SOD levels in the cultured supernatant were increased. Moreover, MUC4 silencing or ERK signaling pathway inactivation may decrease the formation of CaOx crystals. Conclusion: Taken together, silencing of MUC4 can inactivate the ERK signaling pathway and further restrain oxidative stress and CaOx crystal formation in RTEC. Thus, MUC4 represents a potential investigative focus target in nephrolithiasis.

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Oxidative Stress and Cell Senescence Combine to Cause Maximal Renal Tubular Epithelial Cell Dysfunction and Loss in an in vitro Model of Kidney Disease

Cited by 55 publications

References 60 publications

Protection against oxidative stress-induced apoptosis in kidney epithelium by Angelica and Astragalus

Protection against oxidative stress-induced apoptosis in kidney epithelium by Angelica and Astragalus

Resveratrol Protects against High-Fat Diet Induced Renal Pathological Damage and Cell Senescence by Activating SIRT1

Mucin 4 Gene Silencing Reduces Oxidative Stress and Calcium Oxalate Crystal Formation in Renal Tubular Epithelial Cells Through the Extracellular Signal-Regulated Kinase Signaling Pathway in Nephrolithiasis Rat Model

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