scholarly journals Obeticholic acid ameliorates hepatorenal syndrome in ascitic cirrhotic rats by down-regulating the renal 8-iso-PGF2α-activated COX-TXA2 pathway

2020 ◽  
Vol 134 (15) ◽  
pp. 2055-2073
Author(s):  
Yu-Lien Tsai ◽  
Chih-Wei Liu ◽  
Chien-Fu Hsu ◽  
Chia-Chang Huang ◽  
Ming-Wei Lin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hepatorenal Syndrome ◽  
Rat Kidney ◽  
Kidney Injury ◽  
Tubular Damage ◽  
Obeticholic Acid ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Duct Ligation ◽  
Renal Tubular

Abstract Backgrounds/Aims: The present study explores the potential of chronic treatment with the Foresaid X receptor (FXR) agonist obeticholic acid (OCA), which inhibits oxidative stress-related pathogenesis, in ascitic cirrhotic rats with hepatorenal syndrome (HRS) developed 6 weeks after bile duct ligation (BDL). Methods: Systemic, splanchnic, and renal hemodynamics and pathogenic cascades were measured in ascitic BDL and sham rats receiving 2-weeks of either vehicle or OCA treatments (sham-OCA and BDL-OCA groups), and NRK-52E cells, rat kidney tubular epithelial cells. Results: Chronic OCA treatment significantly normalized portal hypertension, glomerular filtration rate, urine output, renal blood flow; decreased ascites, renal vascular resistance, serum creatinine, and the release of renal tubular damage markers, including urinary neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury moleculae-1 (uKim-1) in BDL-OCA rats. In the BDL group, inhibition of the renal oxidative stress (8-iso-PGF2α)-activated cyclooxygenase-thromboxane A2 [COX-TXA2] pathway, apoptosis, and tubular injury accompanied by a decrease in hyper-responsiveness to the vasoconstrictor 8-iso-PGF2α in perfused kidneys. In vitro experiments revealed that 8-iso-PGF2α induced oxidative stress, release of reactive oxygen species, and cell apoptosis, which were reversed by concomitant incubation with the FXR agonist. Conclusions: Through the inhibition of renal 8-iso-PGF2α production and the down-regulation of the COX-TXA2 pathway, our study suggests that chronic OCA treatment can ameliorate the HRS in ascitic cirrhotic rats. Thus, OCA is an agent with antioxidative stress, antivasoconstrictive, antiapoptotic properties which benefit ascitic, cirrhotic rats with systemic, hepatic, and renal abnormalities.

Pro-Apoptotic Effects of Plasma from Patients with Cardiorenal Syndrome on Human Tubular Cells

2015 ◽  
Vol 41 (6) ◽  
pp. 474-484 ◽  
Author(s):  
Grazia Maria Virzì ◽  
Massimo de Cal ◽  
Sonya Day ◽  
Alessandra Brocca ◽  
Dinna N. Cruz ◽  
...  
Keyword(s):  
Kidney Injury ◽  
Cardiorenal Syndrome ◽  
Tubular Damage ◽  
Protein Levels ◽  
Proinflammatory Mediators ◽  
Apoptotic Activity ◽  
Renal Tubular ◽  
Apoptotic Effects ◽  
Time Of Admission

Background: The pathophysiology of Cardiorenal Syndrome Type 1 (CRS1) is widely studied, although the mechanisms by which renal tubular epithelial cells (TECs) cease to proliferate and embark upon terminal differentiation, following the initial insult of heart failure (HF), remain a key target. This study seeks to provide insight into the pathophysiological pathways in CRS1; we evaluated in vitro the effects of CRS1 plasma on TECs. Methods: We enrolled 40 acute HF patients and 15 controls (CTR) without HF or acute kidney injury (AKI). Ten out of 40 HF patients exhibited AKI at the time of admission for HF or developed AKI during hospitalization and were classified as CRS1. In vitro, cell viability, DNA fragmentation and caspase-3 levels were investigated in TECs incubated with HF, CRS1, and CTR plasma. We assessed inflammatory cytokines and NGAL expression at the gene and protein levels. Results: We observed a marked pro-apoptotic activity and a significantly increased in vitro level of apoptosis in TECs incubated with plasma from CRS1 patients compared to HF and CTR (p < 0.01). In the CRS1 group, the mRNA expression of IL-6, IL-18 and NGAL resulted significantly higher in TECs incubated with CRS1 plasma compared with those incubated with plasma from HF and CTR (p < 0.01). IL-6, IL-18, NGAL, and RANTES levels were significantly higher in TECs supernatant incubated with CRS1 plasma compared with HF patients and CTR plasma (p < 0.01). Conclusion: In vitro exposure to plasma from CRS1 patients altered the expression profile of TECs characterized by increases in proinflammatory mediators, release of tubular damage markers, and apoptosis.

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 Curcumin-Loaded Nanoparticles Protect Against Rhabdomyolysis-Induced Acute Kidney Injury

2017 ◽  
Vol 43 (5) ◽  
pp. 2143-2154 ◽  
Author(s):  
Xiaoling Chen ◽  
Jian Sun ◽  
Hailun Li ◽  
Hongwu Wang ◽  
Yongtao Lin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Treatment Efficacy ◽  
Kidney Injury ◽  
In Vivo Studies ◽  
Renal Tubules ◽  
Drug Release Profile ◽  
Renal Tubular

Background/Aims: Rhabdomyolysis (RM) is a potentially life-threatening condition that results from the breakdown of muscle and consequent release of toxic compounds into circulation. The most common and severe complication of RM is acute kidney injury (AKI). This study aimed to evaluate the efficacy and mechanisms of action of curcumin-loaded nanoparticles (Cur-NP) for treatment of RM-induced AKI. Methods: Curcumin-NP was synthesized using the nanocarrier distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG) to achieve a prolonged and constant drug release profile compared with the curcumin-free group. The anti-AKI effects of Curcumin-NP were examined both in vitro (myoglobin-treated renal tubular epithelial HK-2 cells) and in vivo (glycerol-induced AKI model). Results: Our results indicated that Curcumin-NP reversed oxidative stress, growth inhibition and cell apoptosis accompanied with down-regulation of apoptotic markers Caspase-3 and GRP-78 in vitro. In vivo studies revealed enhanced AKI treatment efficacy with Curcumin-NP as characterized by reduced serum creatine phosphokinase (CPK), creatinine (Cr) and urea and less severe histological damage in renal tubules. In addition, kidney tissues from Curcumin-NP-treated AKI rats exhibited reduced oxidative stress, apoptosis, and cleaved Capase-3 and GRP-78 expression. Conclusion: Our results suggest that nanoparticle-loaded curcumin enhances treatment efficacy for RM-induced AKI both in vitro and in vivo.

scholarly journals Protective role of DJ-1 in endotoxin-induced acute kidney injury

2020 ◽  
Vol 319 (4) ◽  
pp. F654-F663 ◽  
Author(s):  
Joseph Leeds ◽  
Yogesh Scindia ◽  
Valentina Loi ◽  
Ewa Wlazlo ◽  
Elizabeth Ghias ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Collecting Duct ◽  
Kidney Injury ◽  
Protective Role ◽  
In Vivo Model ◽  
Renal Tubules ◽  
Death Domain ◽  
Renal Tubular

Acute kidney injury (AKI) is a frequent complication of sepsis and an important cause of morbidity and mortality worldwide. A cornerstone of sepsis-associated AKI is dysregulated inflammation, leading to increased tissue oxidative stress and free radical formation, which leads to multiple forms of cell death. DJ-1 is a peroxiredoxin protein with multiple functions, including its ability to control cellular oxidative stress. Although DJ-1 is expressed prominently by renal tubules, its role in AKI has not been investigated. In the present study, we examined the effect of DJ-1 deficiency in a murine model of endotoxin-induced AKI. Endotoxemia induced greater kidney injury in DJ-1-deficient mice. Furthermore, DJ-1 deficiency increased renal oxidative stress associated with increased renal tubular apoptosis and with expression of death domain-associated protein (DAXX). Similar to the in vivo model, in vitro experiments using a medullary collecting duct cell line (mIMCD3) and cytotoxic serum showed that serum obtained from wild-type mice resulted in increased expression of s100A8/s100A9, DAXX, and apoptosis in DJ-1-deficient mIMCD3 cells. Our findings demonstrate a novel renal protective role for renal tubular DJ-1 during endotoxemia through control of oxidative stress, renal inflammation, and DAXX-dependent apoptosis.

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 Maresin 1 Attenuates Lipopolysaccharide-Induced Acute Kidney Injury via Inhibiting NOX4/ROS/NF-κB Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiameng Li ◽  
Zhuyun Zhang ◽  
Liya Wang ◽  
Luojia Jiang ◽  
Zheng Qin ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Signaling Pathway ◽  
Kidney Injury ◽  
Lipid Mediator ◽  
Tubular Damage ◽  
Omega 3 ◽  
Nitrogen Levels ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Maresin 1

Sepsis-associated acute kidney injury (S-AKI) is a common complication in hospitalized and critically ill patients, which increases the risk of multiple comorbidities and is associated with extremely high mortality. Maresin 1 (MaR1), a lipid mediator derived from the omega-3 fatty acid docosahexaenoic acid has been reported to protect against inflammation and promote the regression of acute inflammation. This study proposed to systematically investigate the renoprotective effects and potential molecular mechanism of MaR1 in septic acute kidney injury. We established a S-AKI animal model by a single intraperitoneal injection of lipopolysaccharide (LPS), 10 mg/kg, on male C57BL/6J mice. LPS-stimulated (100 μg/ml) mouse kidney tubular epithelium cells (TCMK-1) were used to simulate septic AKI in vitro. The results showed that pretreatment with MaR1 significantly reduced serum creatinine and blood urea nitrogen levels as well as tubular damage scores and injury marker neutrophil gelatinase-associated lipocalin in septic AKI mice. Meanwhile, MaR1 administration obviously diminished pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, and MCP-1), downregulated BAX and cleaved caspase-3 expression, and upregulated BCL-2 expression in the injured kidney tissues and TCMK-1 cells. In addition, MaR1 reduced malondialdehyde production and improved the superoxide dismutase activity of renal tissues while inhibiting reactive oxygen species (ROS) production and protecting the mitochondria. Mechanistically, LPS stimulated the expression of the NOX4/ROS/NF-κB p65 signaling pathway in S-AKI kidneys, while MaR1 effectively suppressed the activation of the corresponding pathway. In conclusion, MaR1 attenuated kidney inflammation, apoptosis, oxidative stress, and mitochondrial dysfunction to protect against LPS-induced septic AKI via inhibiting the NOX4/ROS/NF-κB p65 signaling pathway.

Neutrophil Gelatinase-Associated Lipocalin for the Early Prediction of Acute Kidney Injury in ST-Segment Elevation Myocardial Infarction Patients Treated with Primary Percutaneous Coronary Intervention

2020 ◽  
Vol 10 (3) ◽  
pp. 154-161
Author(s):  
Ilan Merdler ◽  
Keren-Lee Rozenfeld ◽  
David Zahler ◽  
Moshe Shtark ◽  
Ilana Goldiner ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Kidney Injury ◽  
Sensitivity And Specificity ◽  
Kidney Injury ◽  
Coronary Intervention ◽  
Tubular Damage ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Plasma Ngal ◽  
Renal Tubular ◽  
Neutrophil Gelatinase

Introduction and Objective: Neutrophil gelatinase-associated lipocalin (NGAL), a glycoprotein released by renal tubular cells, can be used as a marker of early tubular damage. We evaluated plasma NGAL level utilization for the identification of acute kidney injury (AKI) among ST-elevation myocardial infarction (STEMI) patients undergoing primary coronary intervention (PCI). Methods: 131 STEMI patients treated with PCI were prospectively included. Plasma NGAL levels were drawn prior to PCI (0 h) and 24 h afterwards. AKI was defined per KDIGO criteria of serum creatinine increase. Receiver-operating characteristic (ROC) methods were used to identify optimal sensitivity and specificity for the observed NGAL range. Results: Overall AKI incidence was 14%. NGAL levels were significantly higher for patients with AKI at both 0 h (164 ± 42 vs. 95 ± 30; p < 0.001) and 24 h (142 ± 41 vs. 93 ± 36; p < 0.001). Per ROC curve analysis, an optimal cutoff value of NGAL (>120 ng/mL) predicted AKI with 80% sensitivity and specificity (AUC 0.881, 95%, CI 0.801–0.961, p < 0.001). In a multivariate logistic regression model, NGAL levels were independently associated with AKI at 0 h (OR 1.044, 95% CI 1.013–1.076; p = 0.005) and 24 h (OR 1.018, 95% CI 1.001–1.036; p = 0.04). Conclusions: Elevated NGAL levels, suggesting renal tubular damage, are independently associated with AKI in STEMI patients undergoing primary PCI.

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.

Acute kidney injury and renal tubular damage in children with type 1 diabetes mellitus onset

2021 ◽  
Author(s):  
Pierluigi Marzuillo ◽  
Dario Iafusco ◽  
Angela Zanfardino ◽  
Stefano Guarino ◽  
Alessia Piscopo ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Biochemical Parameters ◽  
Kidney Injury ◽  
Fractional Excretion ◽  
Tubular Damage ◽  
Renal Tubular Damage ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Renal Tubular ◽  
Beta 2 Microglobulin ◽  
Physiological And Biochemical

Abstract Context Acute kidney injury(AKI) and renal tubular damage(RTD), especially if complicated by acute tubular necrosis (ATN), could increase the risk of later chronic kidney disease. No prospective studies on AKI and RTD in children with type1diabetes mellitus(T1DM) onset are available. Objectives to evaluate the AKI and RTD prevalence, and their rate and timing of recovery in children with T1DM onset. Design prospective study. Settings and patients: 185children were followed up after 14days from T1DM onset. The patients who did not recover from AKI/RTD were followed-up 30 and 60days later. Main outcome measures AKI was defined according to the KDIGO criteria. RTD was defined by abnormal urinary beta-2-microglobulin and/or neutrophil gelatinase-associated lipocalin and/or tubular reabsorption of phosphate&lt;85% and/or fractional excretion of Na(FENa)&gt;2%. ATN was defined by RTD+AKI, prerenal-(P-)AKI by AKI+FENa&lt;1% while acute tubular damage(ATD) by RTD without AKI. Results Prevalence of diabetic ketoacidosis(DKA) and AKI were 51.4% and 43.8% respectively. Prevalence of AKI in T1DM patients with and without DKA was 65.2% and 21.1%. 33.3% reached AKI stage2 and 66.7% of patients reached AKI stage1. RTD was evident in 136/185(73.5%) patients (32.4% showed ATN; 11.4% P-AKI; 29.7% ATD). All patients with DKA or AKI presented with RTD. The physiological and biochemical parameters of AKI and RTD were normal again in all patients. The former within 14days and the latter within 2months, respectively. Conclusions Most patients with T1DM onset may develop AKI and/or RTD, especially if presenting with DKA. Over time the physiological and biochemical parameters of AKI/RTD normalize in all patients.

scholarly journals PICK1 Deficiency Exacerbates Sepsis-Associated Acute Kidney Injury

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Qian Dou ◽  
Hang Tong ◽  
Yichun Yang ◽  
Han Zhang ◽  
Hua Gan
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Epithelial Cells ◽  
Kidney Injury ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Renal Tubular ◽  
Induced Apoptosis

We performed in vitro and in vivo experiments to explore the role of protein kinase C-binding protein 1 (PICK1), an intracellular transporter involved in oxidative stress-related neuronal diseases, in sepsis-related acute kidney injury (AKI). Firstly, PCR, western blotting, and immunohistochemistry were used to observe the expression of PICK1 after lipopolysaccharide- (LPS-) induced AKI. Secondly, by inhibiting PICK1 in vivo and silencing PICK1 in vitro, we further explored the effect of PICK1 on AKI. Finally, the relationship between PICK1 and oxidative stress and the related mechanisms were explored. We found that the expression of PICK1 was increased in LPS-induced AKI models both in vitro and in vivo. PICK1 silencing significantly aggravated LPS-induced apoptosis, accompanied by ROS production in renal tubular epithelial cells. FSC231, a PICK1-specific inhibitor, aggravated LPS-induced kidney injury. Besides, NAC (N-acetylcysteine), a potent ROS scavenger, significantly inhibited the PICK1-silencing-induced apoptosis. In conclusion, PICK1 might protect renal tubular epithelial cells from LPS-induced apoptosis by reducing excessive ROS, making PICK1 a promising preventive target in LPS-induced AKI.

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