scholarly journals Renal Tubular Epithelial TRPA1 Acts as An Oxidative Stress Sensor to Mediate Ischemia-Reperfusion-Induced Kidney Injury through MAPKs/NF-κB Signaling

2021 ◽  
Vol 22 (5) ◽  
pp. 2309 ◽  
Author(s):  
Chung-Kuan Wu ◽  
Chia-Lin Wu ◽  
Tzong-Shyuan Lee ◽  
Yu Ru Kou ◽  
Der-Cherng Tarng
Keyword(s):  
Oxidative Stress ◽  
Transient Receptor Potential ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Tubular Injury ◽  
Stress Sensor ◽  
Renal Tubular Cells ◽  
Renal Tubular

Oxidative stress and inflammation play important roles in the pathophysiology of acute kidney injury (AKI). Transient receptor potential ankyrin 1 (TRPA1) is a Ca2+-permeable ion channel that is sensitive to reactive oxygen species (ROS). The role of TRPA1 in AKI remains unclear. In this study, we used human and animal studies to assess the role of renal TRPA1 in AKI and to explore the regulatory mechanism of renal TRPA1 in inflammation via in vitro experiments. TRPA1 expression increased in the renal tubular epithelia of patients with AKI. The severity of tubular injury correlated well with tubular TRPA1 or 8-hydroxy-2′-deoxyguanosine expression. In an animal model, renal ischemia-reperfusion injury (IR) increased tubular TRPA1 expression in wild-type (WT) mice. Trpa1−/− mice displayed less IR-induced tubular injury, oxidative stress, inflammation, and dysfunction in kidneys compared with WT mice. In the in vitro model, TRPA1 expression increased in renal tubular cells under hypoxia-reoxygenation injury (H/R) conditions. We demonstrated that H/R evoked a ROS-dependent TRPA1 activation, which elevated intracellular Ca2+ level, increased NADPH oxidase activity, activated MAPK/NF-κB signaling, and increased IL-8. Renal tubular TRPA1 may serve as an oxidative stress sensor and a crucial regulator in the activation of signaling pathways and promote the subsequent transcriptional regulation of IL-8. These actions might be evident in mice with IR or patients with AKI.

scholarly journals In Vivo and In Vitro Evaluation of Urinary Biomarkers in Ischemia/Reperfusion-Induced Kidney Injury

2021 ◽  
Vol 22 (21) ◽  
pp. 11448
Author(s):  
Keiko Hosohata ◽  
Denan Jin ◽  
Shinji Takai
Keyword(s):  
Oxidative Stress ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Experimental Models ◽  
Left Renal Artery ◽  
Tubular Injury ◽  
Renal Tubular ◽  
High Level

Oxidative stress plays an important role in the pathophysiology of acute kidney injury (AKI). Previously, we reported that vanin-1, which is involved in oxidative stress, is associated with renal tubular injury. This study was aimed to determine whether urinary vanin-1 is a biomarker for the early diagnosis of AKI in two experimental models: in vivo and in vitro. In a rat model of AKI, ischemic AKI was induced in uninephrectomized rats by clamping the left renal artery for 45 min and then reperfusing the kidney. On Day 1 after renal ischemia/reperfusion (I/R), serum creatinine (SCr) in I/R rats was higher than in sham-operated rats, but this did not reach significance. Urinary N-acetyl-β-D-glucosaminidase (NAG) exhibited a significant increase but decreased on Day 2 in I/R rats. In contrast, urinary vanin-1 significantly increased on Day 1 and remained at a significant high level on Day 2 in I/R rats. Renal vanin-1 protein decreased on Days 1 and 3. In line with these findings, immunofluorescence staining demonstrated that vanin-1 was attenuated in the renal proximal tubules of I/R rats. Our in vitro results confirmed that the supernatant from HK-2 cells under hypoxia/reoxygenation included significantly higher levels of vanin-1 as well as KIM-1 and NGAL. In conclusion, our results suggest that urinary vanin-1 might be a potential novel biomarker of AKI induced by I/R.

scholarly journals The Predictive Role of the Biomarker Kidney Molecule-1 (KIM-1) in Acute Kidney Injury (AKI) Cisplatin-Induced Nephrotoxicity

2019 ◽  
Vol 20 (20) ◽  
pp. 5238 ◽  
Author(s):  
Daniela Maria Tanase ◽  
Evelina Maria Gosav ◽  
Smaranda Radu ◽  
Claudia Florida Costea ◽  
Manuela Ciocoiu ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Injury ◽  
In Vivo Studies ◽  
Renal Tubular Cells ◽  
Renal Tubular ◽  
Induced Apoptosis ◽  
Kidney Injury Molecule 1

Acute kidney injury (AKI) following platinum-based chemotherapeutics is a frequently reported serious side-effect. However, there are no approved biomarkers that can properly identify proximal tubular injury while routine assessments such as serum creatinine lack sensitivity. Kidney-injury-molecule 1 (KIM-1) is showing promise in identifying cisplatin-induced renal injury both in vitro and in vivo studies. In this review, we focus on describing the mechanisms of renal tubular cells cisplatin-induced apoptosis, the associated inflammatory response and oxidative stress and the role of KIM-1 as a possible biomarker used to predict cisplatin associated AKI.

scholarly journals Isoliquiritigenin attenuates LPS-induced acute kidney injury through suppression of HMGB1 pathway in renal tubular against ferritinophagy

2020 ◽  
Author(s):  
Yun Tang ◽  
Yanmei Wang ◽  
Chan Wang ◽  
Meidie Yu ◽  
Li Li ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Renal Dysfunction ◽  
Kidney Injury ◽  
Tubular Injury ◽  
Renal Tubular Cells ◽  
Septic Acute Kidney Injury ◽  
Life Threatening ◽  
Renal Tubular

Abstract Septic acute kidney injury (AKI) mainly results in life-threatening renal dysfunction involving renal tubular injury to bring heavy burden to patients in intensive care unit (ICU). However, there is still a lack of therapy to prevent septic AKI effectively and inexpensive. To observe the role and novel mechanism of isoliquiritigenin (ISL) which isolated from the roots of licorice in septic AKI, we used LPS to induce renal tubular injury upon septic AKI both in vitro and in vivo. 50mg/kg ISL and 5 mg/kg Ferrostatin-1 were once given to the male C57BL/6 mice one hour before 1 mg/kg LPS i.p injection. 50 μM and 100 μM ISL respectively pre-treat the human renal tubular cells 5 hrs before 2 μg/ml LPS stimulation. We found ISL pretreatment apparently reversed LPS-induced renal dysfunction and ameliorated murine renal tubular injury by suppression HMGB1 pathway. Furthermore, we observed that LPS induced autophagy and ferroptosis in renal tubular, whereas ISL pretreatment significantly suppress autophagy and ferroptosis of renal tubular both in vitro and in vivo. Mechanically, autophagy activated ferroptosis via NCOA4-mediated ferritinophagy. Moreover, HMGB1 is required for ferritinophagy in renal tubular. ISL treatment inhibited the expression of HMGB1. Taken together, these results suggest that ISL protects LPS-induced acute kidney injury through suppression of HMGB1 pathway in renal tubular against ferritinophagy.

Abstract P544: Osteopontin Deficiency Decreases Autophagy and Exacerbates Tubular Injury in Acute Kidney Injury Induced by Folic Acid

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Tomoaki Nagao ◽  
Takafumi Okura ◽  
Akiko Tanino ◽  
Ken-ichi Miyoshi ◽  
Masayoshi Kukida ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Folic Acid ◽  
Kidney Injury ◽  
Immunohistochemical Analysis ◽  
Tubular Injury ◽  
Histological Changes ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular

Osteopontin (OPN), a secreted glycosylated phosphoprotein and pro-inflammatory cytokine, has been implicated in the pathology of several renal conditions, especially renal fibrosis in chronic kidney disease. OPN is slightly expressed in renal tubular cells in normal condition, but after acute tubular injury, OPN is highly induced in these cells. However, the role of induced OPN is still unclear. The aim of this study was to clarify the roles of OPN in acute kidney injury (AKI). AKI was induced in wild type (WT) and OPN knockout (KO) mice by using folic acid (FA) injection (0.35mg/kg). After 2days of injection, 34% of WT mice died, whereas 54% of KO died from renal failure. Kidneys from survived mice were removed and the renal histological changes, protein expression were examined. BUN and Creatinine levels were markedly elevated in WT-AKI and KO-AKI mice (BUN: WT-sham; 25.7±4.7mg/dl, WT-AKI; 315.0±173.2mg/dl, KO-AKI; 337.7±163.7mg/dl, Creatinine: WT-sham; 0.08±0.03 mg/dl, WT-AKI; 1.60±0.87 mg/dl, KO-AKI; 1.80±0.94 mg/dl). Renal OPN mRNA expression was increased in WT-AKI mice compared to WT-sham mice (p<0.05). High levels of OPN expression in renal tubular cells were induced in WT-AKI mice. TUNEL positive tubular cells were increased in KO-AKI mice compared to WT-AKI mice. In immunohistochemical analysis, Kidney injury molecules 1 (Kim-1) positive tubular cells were also highly increased in KO-AKI mice compared to WT-AKI mice. In contrast, LC3B (autophagy related protein) positive tubular cells were decreased in KO-AKI mice compared to WT-AKI mice. These results indicate that OPN deficiency exacerbates tubular injury via through the inhibiting autophagy in folic acid induced AKI mice.

Sestrin-2 and BNIP3 regulate autophagy and mitophagy in renal tubular cells in acute kidney injury

2013 ◽  
Vol 305 (4) ◽  
pp. F495-F509 ◽  
Author(s):  
Masayuki Ishihara ◽  
Madoka Urushido ◽  
Kazu Hamada ◽  
Tatsuki Matsumoto ◽  
Yoshiko Shimamura ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Light Chain ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Tubules ◽  
Dependent Manner ◽  
Renal Tubular

Autophagy is a cellular recycling process induced in response to many types of stress. However, little is known of the signaling pathways that regulate autophagy during acute kidney injury (AKI). Bcl-2/adenovirus E1B 19 kDa-interacting protein (BNIP)3 and sestrin-2 are the target proteins of hypoxia-inducible factor (HIF)-1α and p53, respectively. The aim of this study was to investigate the roles of BNIP3 and sestrin-2 in oxidative stress-induced autophagy during AKI. We used rat ischemia-reperfusion injury and cultured renal tubular (NRK-52E) cells as in vivo and in vitro models of AKI, respectively. Renal ischemia-reperfusion injury upregulated the expression of BNIP3 and sestrin-2 in the proximal tubules, as measured by immunohistochemical staining and Western blot analysis. In vitro, NRK-52E cells exposed to hypoxia showed increased expression of BNIP3 mRNA and protein in a HIF-1α-dependent manner. In contrast, sestrin-2 mRNA and protein expression were upregulated in a p53-dependent manner after exposure to oxidative stress (exogenous H2O2). NRK-52E cells stably transfected with a fusion protein between green fluorescent protein and light chain 3 were used to investigate autophagy. Overexpression of BNIP3 or sestrin-2 in these cells induced light chain 3 expression and formation of autophagosomes. Interestingly, BNIP3-induced autophagosomes were mainly localized to the mitochondria, suggesting that this protein selectively induces mitophagy. These observations demonstrate that autophagy is induced in renal tubules by at least two independent pathways involving p53-sestrin-2 and HIF-1α-BNIP3, which may be activated by different types of stress to protect the renal tubules during AKI.

scholarly journals Recombinant Long-Acting Thioredoxin Ameliorates AKI to CKD Transition via Modulating Renal Oxidative Stress and Inflammation

2021 ◽  
Vol 22 (11) ◽  
pp. 5600
Author(s):  
Kento Nishida ◽  
Hiroshi Watanabe ◽  
Ryota Murata ◽  
Kai Tokumaru ◽  
Rui Fujimura ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Human Albumin ◽  
M Cell ◽  
Protein Levels ◽  
Renal Tubular Cells ◽  
Redox Active ◽  
Renal Tubular ◽  
Long Acting

An effective strategy is highly desirable for preventing acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Thioredoxin-1 (Trx), a redox-active protein that has anti-oxidative and anti-inflammatory properties, would be a candidate for this but its short half-life limits its clinical application. In this study, we examined the renoprotective effect of long-acting Trx that is comprised of human albumin and Trx (HSA-Trx) against AKI to CKD transition. AKI to CKD mice were created by renal ischemia-reperfusion (IR). From day 1 to day 14 after renal IR, the recovery of renal function was accelerated by HSA-Trx administration. On day 14, HSA-Trx reduced renal fibrosis compared with PBS treatment. At the early phase of fibrogenesis (day 7), HSA-Trx treatment suppressed renal oxidative stress, pro-inflammatory cytokine production and macrophage infiltration, thus ameliorating tubular injury and fibrosis. In addition, HSA-Trx treatment inhibited G2/M cell cycle arrest and apoptosis in renal tubular cells. While renal Trx protein levels were decreased after renal IR, the levels were recovered by HSA-Trx treatment. Together, HSA-Trx has potential for use in the treatment of AKI to CKD transition via its effects of modulating oxidative stress and inflammation.

scholarly journals Role of TRPA1 in Tissue Damage and Kidney Disease

2021 ◽  
Vol 22 (7) ◽  
pp. 3415
Author(s):  
Chung-Kuan Wu ◽  
Ji-Fan Lin ◽  
Tzong-Shyuan Lee ◽  
Yu Ru Kou ◽  
Der-Cherng Tarng
Keyword(s):  
Kidney Disease ◽  
Tissue Damage ◽  
Animal Studies ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Cell Types ◽  
Renal Tubular

TRPA1, a nonselective cation channel, is expressed in sensory afferent that innervates peripheral targets. Neuronal TRPA1 can promote tissue repair, remove harmful stimuli and induce protective responses via the release of neuropeptides after the activation of the channel by chemical, exogenous, or endogenous irritants in the injured tissue. However, chronic inflammation after repeated noxious stimuli may result in the development of several diseases. In addition to sensory neurons, TRPA1, activated by inflammatory agents from some non-neuronal cells in the injured area or disease, might promote or protect disease progression. Therefore, TRPA1 works as a molecular sentinel of tissue damage or as an inflammation gatekeeper. Most kidney damage cases are associated with inflammation. In this review, we summarised the role of TRPA1 in neurogenic or non-neurogenic inflammation and in kidney disease, especially the non-neuronal TRPA1. In in vivo animal studies, TRPA1 prevented sepsis-induced or Ang-II-induced and ischemia-reperfusion renal injury by maintaining mitochondrial haemostasis or via the downregulation of macrophage-mediated inflammation, respectively. Renal tubular epithelial TRPA1 acts as an oxidative stress sensor to mediate hypoxia–reoxygenation injury in vitro and ischaemia–reperfusion-induced kidney injury in vivo through MAPKs/NF-kB signalling. Acute kidney injury (AKI) patients with high renal tubular TRPA1 expression had low complete renal function recovery. In renal disease, TPRA1 plays different roles in different cell types accordingly. These findings depict the important role of TRPA1 and warrant further investigation.

scholarly journals Hyperhomocysteinemia exacerbates ischemia-reperfusion injury-induced acute kidney injury by mediating oxidative stress, DNA damage, JNK pathway, and apoptosis

2021 ◽  
Vol 16 (1) ◽  
pp. 537-543
Author(s):  
Mei Zhang ◽  
Jing Yuan ◽  
Rong Dong ◽  
Jingjing Da ◽  
Qian Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Cell Apoptosis ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Tubular Cell ◽  
Tubular Injury ◽  
Jnk Pathway ◽  
Pathway Activation

Abstract Background Hyperhomocysteinemia (HHcy) plays an important role in the progression of many kidney diseases; however, the relationship between HHcy and ischemia-reperfusion injury (IRI)-induced acute kidney injury (IRI-induced AKI) is far from clear. In this study, we try to investigate the effect and possible mechanisms of HHcy on IRI-induced AKI. Methods Twenty C57/BL6 mice were reared with a regular diet or high methionine diet for 2 weeks (to generate HHcy mice); after that, mice were subgrouped to receive sham operation or ischemia-reperfusion surgery. Twenty four hour after reperfusion, serum creatinine, blood urea nitrogen, and Malondialdehyde (MDA) were measured. H&E staining for tubular injury, western blot for γH2AX, JNK, p-JNK, and cleaved caspase 3, and TUNEL assay for tubular cell apoptosis were also performed. Results Our results showed that HHcy did not influence the renal function and histological structure, as well as the levels of MDA, γH2AX, JNK, p-JNK, and tubular cell apoptosis in control mice. However, in IRI-induced AKI mice, HHcy caused severer renal dysfunction and tubular injury, higher levels of oxidative stress, DNA damage, JNK pathway activation, and tubular cell apoptosis. Conclusion Our results demonstrated that HHcy could exacerbate IRI-induced AKI, which may be achieved through promoting oxidative stress, DNA damage, JNK pathway activation, and consequent apoptosis.

scholarly journals Genetic Polymorphisms of MnSOD Modify the Impacts of Environmental Melamine on Oxidative Stress and Early Kidney Injury in Calcium Urolithiasis Patients

Antioxidants ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 152
Author(s):  
Chia-Chu Liu ◽  
Chia-Fang Wu ◽  
Yung-Chin Lee ◽  
Tsung-Yi Huang ◽  
Shih-Ting Huang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Manganese Superoxide Dismutase ◽  
Kidney Injury ◽  
Normal Function ◽  
Nucleotide Polymorphisms ◽  
Tubular Injury ◽  
Single Nucleotide ◽  
Manganese Superoxide ◽  
Calcium Urolithiasis ◽  
Renal Tubular

Environmental melamine exposure increases the risks of oxidative stress and early kidney injury. Manganese superoxide dismutase (MnSOD), glutathione peroxidase, and catalase can protect the kidneys against oxidative stress and maintain normal function. We evaluated whether their single-nucleotide polymorphisms (SNPs) could modify melamine’s effects. A total of 302 patients diagnosed with calcium urolithiasis were enrolled. All patients provided one-spot overnight urine samples to measure their melamine levels, urinary biomarkers of oxidative stress and renal tubular injury. Median values were used to dichotomize levels into high and low. Subjects carrying the T allele of rs4880 and high melamine levels had 3.60 times greater risk of high malondialdehyde levels than those carrying the C allele of rs4880 and low melamine levels after adjustment. Subjects carrying the G allele of rs5746136 and high melamine levels had 1.73 times greater risk of high N-Acetyl-β-d-glucosaminidase levels than those carrying the A allele of rs5746136 and low melamine levels. In conclusion, the SNPs of MnSOD, rs4880 and rs5746136, influence the risk of oxidative stress and renal tubular injury, respectively, in calcium urolithiasis patients. In the context of high urinary melamine levels, their effects on oxidative stress and renal tubular injury were further increased.

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.

Sign in / Sign up

Export Citation Format

Share Document