scholarly journals Bicalutamide Elicits Renal Damage by Causing Mitochondrial Dysfunction via ROS Damage and Upregulation of HIF-1

2020 ◽  
Vol 21 (9) ◽  
pp. 3400
Author(s):  
Kuan-Chou Chen ◽  
Chang-Rong Chen ◽  
Chang-Yu Chen ◽  
Kai-Yi Tzou ◽  
Chiung-Chi Peng ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Renal Damage ◽  
Mesangial Cells ◽  
Cell Model ◽  
Hypoxia Inducible Factor ◽  
Kidney Injury ◽  
Mitochondrial Potential ◽  
Interacting Protein ◽  
Atp Production

Combined androgen blockade using bicalutamide (Bic) is a therapeutic choice for treating prostate cancer (PCa). However, even at regular clinical dosages, Bic frequently shows adverse effects associated with cardiovascular and renal damage. Previously, we found that Bic selectively damaged mesangial cells compared to tubular cells and in an in vivo rat model, we also found renal damage caused by Bic. In the present study, a rat mesangial cell model was used to further the investigation. Results indicated that Bic enhanced lactate dehydrogenase release, reactive oxygen species (ROS) production, lysosome population and kidney injury molecule-1 and decreased N-cadherin. Bic elicited mitochondrial swelling and reduced the mitochondrial potential, resulting in severe suppression of the oxygen consumption rate (OCR), maximum respiration and ATP production. The hypoxia-inducible factor (HIF)-1 transcriptional activity and messenger RNA were significantly upregulated in dose-dependent manners. The HIF-1 protein reached a peak value at 24 h then rapidly decayed. BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 and cleaved caspase-3 were dose-dependently upregulated by Bic (60 M) and that eventually led to cell apoptosis. It is suggested that Bic induces renal damage via ROS and modulates HIF-1 pathway and clinically, some protective agents like antioxidants are recommended for co-treatment.

miR-125b enhances metastasis and progression of cancer via the TXNIP and HIF1α pathway in pancreatic cancer

2021 ◽  
pp. 1-12
Author(s):  
Pengli Wang ◽  
Dan Zheng ◽  
Hongyang Qi ◽  
Qi Gao
Keyword(s):  
Pancreatic Cancer ◽  
Hypoxia Inducible Factor ◽  
Immunofluorescence Assay ◽  
Luciferase Assay ◽  
Interacting Protein ◽  
Over Expression ◽  
Thioredoxin Interacting Protein ◽  
Cellular Processes ◽  
And Migration

BACKGROUND: MicroRNAs (miRNAs) play potential role in the development of various types of cancer conditions including pancreatic cancer (PC) targeting several cellular processes. Present study was aimed to evaluate function of miR-125b and the mechanism involved in PC. METHODS: Cell migration, MTT and BrdU study was done to establish the migration capability, cell viability and cell proliferation respectively. Binding sites for miR-125b were recognized by luciferase assay, expression of protein by western blot and immunofluorescence assay. In vivo study was done by BALB/c nude xenograft mice for evaluating the function of miR-125b. RESULTS: The study showed that expression of miR-125b was elevated in PC cells and tissues, and was correlated to proliferation and migration of cells. Also, over-expression of miR-125b encouraged migration, metastasis and proliferation of BxPC-3 cells, the suppression reversed it. We also noticed that thioredoxin-interacting protein (TXNIP) was the potential target of miR-125b. The outcomes also suggested that miR-125b governed the expression of TXNIP inversely via directly attaching to the 3′-UTR activating hypoxia-inducible factor 1α (HIF1α). Looking into the relation between HIF1α and TXNIP, we discovered that TXNIP caused the degradation and export of HIF1α by making a complex with it. CONCLUSION: The miR-125b-TXNIP-HIF1α pathway may serve useful strategy for diagnosing and treating PC.

scholarly journals High Glucose and Lipopolysaccharide Prime NLRP3 Inflammasome via ROS/TXNIP Pathway in Mesangial Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Hong Feng ◽  
Junling Gu ◽  
Fang Gou ◽  
Wei Huang ◽  
Chenlin Gao ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Nlrp3 Inflammasome ◽  
High Glucose ◽  
Mesangial Cells ◽  
Central Component ◽  
Dependent Manner ◽  
Glomerular Mesangial Cells ◽  
Interacting Protein

While inflammation is considered a central component in the development in diabetic nephropathy, the mechanism remains unclear. The NLRP3 inflammasome acts as both a sensor and a regulator of the inflammatory response. The NLRP3 inflammasome responds to exogenous and endogenous danger signals, resulting in cleavage of procaspase-1 and activation of cytokines IL-1β, IL-18, and IL-33, ultimately triggering an inflammatory cascade reaction. This study observed the expression of NLRP3 inflammasome signaling stimulated by high glucose, lipopolysaccharide, and reactive oxygen species (ROS) inhibitor N-acetyl-L-cysteine in glomerular mesangial cells, aiming to elucidate the mechanism by which the NLRP3 inflammasome signaling pathway may contribute to diabetic nephropathy. We found that the expression of thioredoxin-interacting protein (TXNIP), NLRP3, and IL-1βwas observed by immunohistochemistry in vivo. Simultaneously, the mRNA and protein levels of TXNIP, NLRP3, procaspase-1, and IL-1βwere significantly induced by high glucose concentration and lipopolysaccharide in a dose-dependent and time-dependent manner in vitro. This induction by both high glucose and lipopolysaccharide was significantly inhibited by N-acetyl-L-cysteine. Our results firstly reveal that high glucose and lipopolysaccharide activate ROS/TXNIP/ NLRP3/IL-1βinflammasome signaling in glomerular mesangial cells, suggesting a mechanism by which inflammation may contribute to the development of diabetic nephropathy.

scholarly journals Evaluation of biomarkers for in vitro prediction of drug-induced nephrotoxicity in RPTEC/TERT1 cells

2020 ◽  
Vol 9 (2) ◽  
pp. 91-100 ◽  
Author(s):  
Xuan Qiu ◽  
Yufa Miao ◽  
Xingchao Geng ◽  
Xiaobing Zhou ◽  
Bo Li
Keyword(s):  
Transcriptional Activation ◽  
Messenger Rna ◽  
Aristolochic Acid ◽  
Kidney Injury ◽  
Drug Induced ◽  
Vitro Assay ◽  
Protein Levels ◽  
Aristolochic Acid I

Abstract There have been intensive efforts to identify in vivo biomarkers that can be used to monitor drug-induced kidney damage before significant impairment occurs. Kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, clusterin, β2-microglobulin and cystatin C (CysC) have been validated as clinical or preclinical biomarkers in urinary and plasma predictive of acute and chronic kidney injuries and diseases. A high-throughput in vitro assay predictive of nephrotoxicity could potentially be implemented in early drug discovery stage to reduce attrition at later stages of drug development. To assess the potential of these known in vivo biomarkers for in vitro evaluation of drug-induced nephrotoxicity, we selected four nephrotoxic agents (cisplatin, cyclosporin, aristolochic acid I and gentamicin) and detected their effects on the protein levels of nephrotoxic biomarkers in RPTEC/TERT1 cells. The protein levels of clusterin, CysC, GSTπ and TIMP-1 significantly increased in the conditioned media of RPTEC/TERT1 cells treated with cisplatin, cyclosporin, aristolochic acid I and gentamicin. The messenger RNA levels of clusterin, CysC, GSTπ and TIMP-1 also increased in RPTEC/TERT1 cells treated with cisplatin, cyclosporin, aristolochic acid I and gentamicin, indicating that drug-induced upregulation involves transcriptional activation. Taken together, the results clearly demonstrate that among the known in vivo nephrotoxic biomarkers, clusterin, CysC, GSTπ and TIMP-1 can be effectively used as in vitro biomarkers for drug-induced nephrotoxicity in RPTEC/TERT1 cells.

scholarly journals Inhibitor of DNA Binding 1 Is Induced during Kidney Ischemia-Reperfusion and Is Critical for the Induction of Hypoxia-Inducible Factor-1α

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Dan Wen ◽  
Yan-Fang Zou ◽  
Yao-Hui Gao ◽  
Qian Zhao ◽  
Yin-Yin Xie ◽  
...  
Keyword(s):  
Dna Binding ◽  
Ischemia Reperfusion ◽  
Hypoxia Inducible Factor ◽  
Kidney Injury ◽  
Mrna Levels ◽  
Hypoxia Inducible Factor 1 ◽  
Renal Tubular ◽  
Inhibitor Of Dna Binding

In this study, rat models of acute kidney injury (AKI) induced by renal ischemia-reperfusion (I/R) and HK-2 cell models of hypoxia-reoxygenation (H/R) were established to investigate the expression of inhibitor of DNA binding 1 (ID1) in AKI, and the regulation relationship between ID1 and hypoxia-inducible factor 1 alpha (HIF-1α). Through western blot, quantitative real-time PCR, immunohistochemistry, and other experiment methods, the induction of ID1 after renal I/R in vivo was observed, which was expressed mainly in renal tubular epithelial cells (TECs). ID1 expression was upregulated in in vitro H/R models at both the protein and mRNA levels. Via RNAi, it was found that ID1 induction was inhibited with silencing of HIF-1α. Moreover, the suppression of ID1 mRNA expression could lead to decreased expression and transcription of HIF-1αduring hypoxia and reoxygenation. In addition, it was demonstrated that both ID1 and HIF-1αcan regulate the transcription of twist. This study demonstrated that ID1 is induced in renal TECs during I/R and can regulate the transcription and expression of HIF-1α.

scholarly journals Lipidomics Reveals Cisplatin-Induced Renal Lipid Alterations during Acute Kidney Injury and Their Attenuation by Cilastatin

2021 ◽  
Vol 22 (22) ◽  
pp. 12521
Author(s):  
Estefanía Moreno-Gordaliza ◽  
Maria Dolores Marazuela ◽  
Óscar Pastor ◽  
Alberto Lázaro ◽  
María Milagros Gómez-Gómez
Keyword(s):  
Acute Kidney Injury ◽  
Renal Damage ◽  
Preventive Intervention ◽  
Kidney Injury ◽  
Major Complication ◽  
Kidney Cortex ◽  
In Vivo Models ◽  
Lipid Species

Nephrotoxicity is a major complication of cisplatin-based chemotherapy, leading to acute kidney injury in ca. 30% of patients, with no preventive intervention or treatment available for clinical use. Cilastatin has proved to exert a nephroprotective effect for cisplatin therapies in in vitro and in vivo models, having recently entered clinical trials. A deeper understanding at the molecular level of cisplatin-induced renal damage and the effect of potential protective agents could be key to develop successful nephroprotective therapies and to establish new biomarkers of renal damage and nephroprotection. A targeted lipidomics approach, using LC-MS/MS, was employed for the quantification of 108 lipid species (comprising phospholipids, sphingolipids, and free and esterified cholesterol) in kidney cortex and medulla extracts from rats treated with cisplatin and/or cilastatin. Up to 56 and 63 lipid species were found to be altered in the cortex and medulla, respectively, after cisplatin treatment. Co-treatment with cilastatin attenuated many of these lipid changes, either totally or partially with respect to control levels. Multivariate analysis revealed that lipid species can be used to discriminate renal damage and nephroprotection, with cholesterol esters being the most discriminating species, along with sulfatides and phospholipids. Potential diagnostic biomarkers of cisplatin-induced renal damage and cilastatin nephroprotection were also found.

scholarly journals In vivo mitochondrial matrix proteome profiling reveals RTN4IP1/OPA10 as an antioxidant NADPH oxidoreductase

2021 ◽  
Author(s):  
Isaac Park ◽  
Kwang-eun Kim ◽  
Jeesoo Kim ◽  
Subin Bae ◽  
Minkyo Jung ◽  
...  
Keyword(s):  
Coenzyme Q ◽  
C2c12 Cells ◽  
Mitochondrial Matrix ◽  
Protein Structure Analysis ◽  
Quinone Oxidoreductase ◽  
Interacting Protein ◽  
Atp Production ◽  
Muscle Tissues ◽  
Muscle Groups

Targeting proximity labeling enzymes to specific cellular locations is a viable strategy for profiling subcellular proteomes. Here, we generated transgenic mice expressing a mitochondrial matrix-targeted ascorbate peroxidase (MAX-Tg) to analyze tissue-specific matrix proteomes. Desthiobiotin-phenol labeling of muscle tissues from MAX-Tg mice allowed for efficient profiling of mitochondrial-localized proteins in these tissues. Comparative analysis of matrix proteomes from MAX-Tg muscle tissues revealed differential enrichment of mitochondrial proteins related to energy production in between different muscle groups. Reticulon 4 interacting protein 1 (RTN4IP1), also known as Optic Atrophy-10 (OPA10), was highly enriched in the cardiac and soleus muscles and was found to localize to the mitochondrial matrix via a strong mitochondrial targeting sequence at its N-terminus. Protein structure analysis revealed that RTN4IP1 is an NADPH oxidoreductase with structural homology to bacterial quinone oxidoreductase. Enzymatic activity assays, interactome analysis, and metabolite profiling confirmed a function for RTN4IP1 in coenzyme Q (CoQ) biosynthesis. Rtn4ip1-knockout C2C12 cells had reduced CoQ9 levels, were vulnerable to oxidative stress, and had decreased oxygen consumption rates and ATP production. Collectively, RTN4IP1 is a mitochondrial antioxidant NADPH oxidoreductase supporting oxidative phosphorylation activity in muscle tissue.

scholarly journals Ethyl Vanillin Protects against Kidney Injury in Diabetic Nephropathy by Inhibiting Oxidative Stress and Apoptosis

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Yuna Tong ◽  
Shan Liu ◽  
Rong Gong ◽  
Lei Zhong ◽  
Xingmei Duan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Cell Apoptosis ◽  
Cell Model ◽  
Critical Role ◽  
Kidney Injury ◽  
Related Factor ◽  
Ethyl Vanillin

Diabetes-induced oxidative stress and apoptosis is regarded as a critical role in the pathogenesis of diabetic nephropathy (DN). Treating diabetes-induced kidney damage and renal dysfunction has been thought a promising therapeutic option to attenuate the development and progression of DN. In this study, we investigated the renoprotective effect of ethyl vanillin (EVA), an active analogue of vanillin isolated from vanilla beans, on streptozotocin- (STZ-) induced rat renal injury model and high glucose-induced NRK-52E cell model. The EVA treatment could strongly improve the deterioration of renal function and kidney cell apoptosis in vivo and in vitro. Moreover, treating with EVA significantly decreased the level of MDA and reactive oxygen species (ROS) and stabilized antioxidant enzyme system in response to oxidative stress by enhancing the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in vivo and in vitro. Furthermore, EVA also markedly suppressed cleaved caspase-3, Bax, and nuclear transcription factor erythroid 2-related factor (Nrf2) expression in STZ-induced rats. Therefore, these results of our investigation provided that EVA might protect against kidney injury in DN by inhibiting oxidative stress and cell apoptosis.

scholarly journals The lncRNA CASC9 alleviates lipopolysaccharide-induced acute kidney injury by regulating the miR-424-5p/TXNIP pathway

2021 ◽  
Vol 49 (8) ◽  
pp. 030006052110374
Author(s):  
Hai-Peng Fan ◽  
Zhi-Xia Zhu ◽  
Jia-Jun Xu ◽  
Yu-Tang Li ◽  
Chun-Wen Guo ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Cancer Susceptibility ◽  
Kidney Injury ◽  
In Vivo Model ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Downstream Target ◽  
Renal Tubular

Objective This study aimed to clarify the mechanism by which the long non-coding RNA cancer susceptibility candidate 9 (CASC9) alleviates sepsis-related acute kidney injury (S-AKI). Methods A lipopolysaccharide (LPS)-induced AKI model was established to simulate S-AKI. HK-2 human renal tubular epithelial cells were treated with LPS to establish an in vitro model, and mice were intraperitoneally injected with LPS to generate an in vivo model. Subsequently, the mRNA expression of inflammatory and antioxidant factors was validated by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Reactive oxygen species (ROS) production was assessed using an assay kit. Apoptosis was detected by western blotting and fluorescence-activated cell sorting. Results CASC9 was significantly downregulated in the LPS-induced AKI model. CASC9 attenuated cell inflammation and apoptosis and enhanced the antioxidant capacity of cells. Regarding the mechanism, miR-424-5p was identified as the downstream target of CASC9, and the interaction between CASC9 and miR-424-5p promoted thioredoxin-interacting protein (TXNIP) expression. Conclusions CASC9 alleviates LPS-induced AKI in vivo and in vitro, and CASC9 directly targets miR-424-5p and further promotes the expression of TXNIP. We have provided a possible reference strategy for the treatment of S-AKI.

scholarly journals Kidney injury by cyclosporine A is aggravated in heme oxygenase-1 deficient mice and involves regulation of microRNAs

2018 ◽  
Author(s):  
Agnieszka Łoboda ◽  
Olga Mucha ◽  
Paulina Podkalicka ◽  
Mateusz Sobczak ◽  
Anna Miksza-Cybulska ◽  
...  
Keyword(s):  
Heme Oxygenase ◽  
Cyclosporine A ◽  
Renal Damage ◽  
Kidney Injury ◽  
Protective Role ◽  
Immunosuppressive Drug ◽  
Heme Oxygenase 1 ◽  
Knock Out ◽  
Deficient Mice

Cyclosporine A (CsA), a widely used immunosuppressive drug, exerts nephrotoxic activities, as demonstrated by increased tubulointerstitial fibrosis, inflammation and podocyte damage. Recently, a number of microRNAs expressed in the kidney have been reported to be elevated during renal damage. Our aim was to investigate the effect of CsA on selected microRNAs in the mouse kidney after CsA treatment. Moreover, as heme oxygenase-1 (HO-1, encoded by the Hmox1 gene) was shown to play a protective role during kidney disorders, we assessed whether HO-1 deficiency in vivo influences the CsA-regulated microRNAs’ expression. We have observed that the pro-fibrotic miR-21 and pro-apoptotic miR-34a expression was upregulated in kidneys of HO-1 deficient mice and it was further enhanced by CsA. Concomitantly, the level of anti-fibrotic microRNAs, belonging to miR-29 and miR-200 families, was down-regulated after CsA treatment. Generally, Hmox1 knock-out (Hmox1–/–) animals were more susceptible to CsA treatment, as the mortality rate was 4 out of 9 Hmox1–/– mice, and increased fibrosis (Tgfb2, Pai1), inflammation (Il6) and apoptosis (Cdkn1a-p21) were noticed in the HO-1 deficient kidneys. In summary, our data demonstrate that CsA induces significant changes in the expression of renal microRNAs and emphasize HO-1 deficiency as an important factor contributing to the CsA-mediated renal toxicity.

scholarly journals Tangshen Formula Attenuates Diabetic Kidney Injury by Imparting Anti-pyroptotic Effects via the TXNIP-NLRP3-GSDMD Axis

2021 ◽  
Vol 11 ◽  
Author(s):  
Nan Li ◽  
Tingting Zhao ◽  
Yongtong Cao ◽  
Haojun Zhang ◽  
Liang Peng ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Kidney Injury ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
Protective Effects ◽  
Interacting Protein ◽  
Diabetic Kidney ◽  
Tangshen Formula

We previously reported that Tangshen formula (TSF), a Chinese herbal medicine for diabetic kidney disease (DKD) therapy, imparts renal protective effects. However, the underlying mechanisms of these effects remain unclear. Pyroptosis is a form of programmed cell death that can be triggered by the NLRP3 inflammasome. Recently, the association between the pyroptosis of renal resident cells and DKD was established, but with limited evidence. This study aimed to investigate whether the renal protective effects of TSF are related to its anti-pyroptotic effect. DKD rats established by right uninephrectomy plus a single intraperitoneal injection of STZ and HK-2 cells stimulated by AGEs were used. In vivo, TSF reduced the 24 h urine protein (24 h UP) of DKD rats and alleviated renal pathological changes. Meanwhile, the increased expression of pyroptotic executor (GSDMD) and NLRP3 inflammasome pathway molecules (NLRP3, caspase-1, and IL-1β) located in the tubules of DKD rats were downregulated with TSF treatment. In vitro, we confirmed the existence of pyroptosis in AGE-stimulated HK-2 cells and the activation of the NLRP3 inflammasome. TSF reduced pyroptosis and NLRP3 inflammasome activation in a dosage-dependent manner. Then, we used nigericin to determine that TSF imparts anti-pyroptotic effects by inhibiting the NLRP3 inflammasome. Finally, we found that TSF reduces reactive oxygen species (ROS) production and thioredoxin-interacting protein (TXNIP) expression in AGE-stimulated HK-2 cells. More importantly, TSF decreased the colocalization of TXNIP and NLRP3, indicating that ROS-TXNIP may be the target of TSF. In summary, the anti-pyroptotic effect via the TXNIP-NLRP3-GSDMD axis may be an important mechanism of TSF for DKD therapy.

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