scholarly journals Repurposing of High-Dose Erythropoietin as a Potential Drug Attenuates Sepsis in Preconditioning Renal Injury

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3133
Author(s):  
Wiwat Chancharoenthana ◽  
Kanyarat Udompronpitak ◽  
Yolradee Manochantr ◽  
Piyawat Kantagowit ◽  
Ponthakorn Kaewkanha ◽  
...  
Keyword(s):  
Renal Injury ◽  
Inflammatory Responses ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Erythropoietin Receptor ◽  
High Dose ◽  
Disease Characteristics ◽  
High Prevalence ◽  
Injury Models ◽  
Inflammatory Effect

Due to (i) the uremia-enhanced sepsis severity, (ii) the high prevalence of sepsis with pre-existing renal injury and (iii) the non-erythropoiesis immunomodulation of erythropoietin (EPO), EPO was tested in sepsis with pre-existing renal injury models with the retrospective exploration in patients. Then, EPO was subcutaneously administered in mice with (i) cecal ligation and puncture (CLP) after renal injury including 5/6 nephrectomy (5/6Nx-CLP) and bilateral nephrectomy (BiNx-CLP) or sham surgery (sham-CLP) and (ii) lipopolysaccharide (LPS) injection, along with testing in macrophages. In patients, the data of EPO administration and the disease characteristics in patients with sepsis-induced acute kidney injury (sepsis-AKI) were evaluated. As such, increased endogenous EPO was demonstrated in all sepsis models, including BiNx-CLP despite the reduced liver erythropoietin receptor (EPOR), using Western blot analysis and gene expression, in liver (partly through hepatocyte apoptosis). A high-dose EPO, but not a low-dose, attenuated sepsis in mouse models as determined by mortality and serum inflammatory cytokines. Furthermore, EPO attenuated inflammatory responses in LPS-activated macrophages as determined by supernatant cytokines and the expression of several inflammatory genes (iNOS, IL-1β, STAT3 and NFκB). In parallel, patients with sepsis-AKI who were treated with the high-dose EPO showed favorable outcomes, particularly the 29-day mortality rate. In conclusion, high-dose EPO attenuated sepsis with preconditioning renal injury in mice possibly through the macrophage anti-inflammatory effect, which might be beneficial in some patients.

scholarly journals TRAF3 Modulation: Novel Mechanism for the Anti-inflammatory Effects of the Vitamin D Receptor Agonist Paricalcitol in Renal Disease

2020 ◽  
Vol 31 (9) ◽  
pp. 2026-2042 ◽  
Author(s):  
Sandra Rayego-Mateos ◽  
Jose Luis Morgado-Pascual ◽  
José Manuel Valdivielso ◽  
Ana Belén Sanz ◽  
Enrique Bosch-Panadero ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Cultured Cells ◽  
Kidney Injury ◽  
Preclinical Model ◽  
Protein Levels ◽  
Inflammatory State ◽  
Anti Inflammatory ◽  
Injury Models ◽  
Inflammatory Effect

BackgroundCKD leads to vitamin D deficiency. Treatment with vitamin D receptor agonists (VDRAs) may have nephroprotective and anti-inflammatory actions, but their mechanisms of action are poorly understood.MethodsModulation of the noncanonical NF-κB2 pathway and its component TNF receptor–associated factor 3 (TRAF3) by the VDRA paricalcitol was studied in PBMCs from patients with ESKD, cytokine-stimulated cells, and preclinical kidney injury models.ResultsIn PBMCs isolated from patients with ESKD, TRAF3 protein levels were lower than in healthy controls. This finding was associated with evidence of noncanonical NF-κB2 activation and a proinflammatory state. However, PBMCs from patients with ESKD treated with paricalcitol did not exhibit these features. Experiments in cultured cells confirmed the link between TRAF3 and NF-κB2/inflammation. Decreased TRAF3 ubiquitination in K48-linked chains and cIAP1-TRAF3 interaction mediated the mechanisms of paricalcitol action.TRAF3 overexpression by CRISPR/Cas9 technology mimicked VDRA’s effects. In a preclinical model of kidney injury, paricalcitol inhibited renal NF-κB2 activation and decreased renal inflammation. In VDR knockout mice with renal injury, paricalcitol prevented TRAF3 downregulation and NF-κB2–dependent gene upregulation, suggesting a VDR-independent anti-inflammatory effect of paricalcitol.ConclusionsThese data suggest the anti-inflammatory actions of paricalcitol depend on TRAF3 modulation and subsequent inhibition of the noncanonical NF-κB2 pathway, identifying a novel mechanism for VDRA’s effects. Circulating TRAF3 levels could be a biomarker of renal damage associated with the inflammatory state.

scholarly journals High-dose ascorbate with low-dose amphotericin B attenuates severity of disease in a model of the reappearance of candidemia during sepsis in the mouse

2015 ◽  
Vol 309 (3) ◽  
pp. R223-R234 ◽  
Author(s):  
Asada Leelahavanichkul ◽  
Poorichaya Somparn ◽  
Tanabodee Bootprapan ◽  
Hongbin Tu ◽  
Pattarin Tangtanatakul ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Mouse Model ◽  
Amphotericin B ◽  
Low Dose ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Sodium Deoxycholate ◽  
High Dose ◽  
Phagocytic Cells

Amphotericin B (Ampho B) is a fungicidal drug that causes cell wall injury. Pharmacological ascorbate induces the extracellular prooxidants, which might enter the Ampho B-induced cell wall porosity and act synergistically. We tested low-dose Ampho B with a short course of pharmacological ascorbate using a mouse model of sepsis preconditioned with an injection of Candida albicans 6 h prior to cecal ligation and puncture (CLP). In this model, candidemia reappeared as early as 6 h after CLP with a predictably high mortality rate. This characteristic mimics sepsis in the phase of immunosuppression in patients. Using the model, at 12- and 18-h post-CLP, we administered isotonic (pH neutralized) pharmacological ascorbate intravenously with low-dose Ampho B or sodium deoxycholate, vehicle-controlled, administered IP. The survival rate of low-dose Ampho B plus ascorbate was 53%, compared with <11% for low-dose Ampho B or high-dose Ampho B alone. In addition, a beneficial effect was demonstrated in terms of kidney damage, liver injury, spleen histopathology, and serum markers at 24 h after CLP. Kidney injury was less severe in low-dose Ampho B plus ascorbate combination therapy due to less severe sepsis. Moreover, ascorbate enhanced the effectiveness of phagocytosis against C. albicans in human phagocytic cells. Taken together, the data indicate that the new mouse model simulates sepsis-induced immunosuppression and that the combination of pharmacological ascorbate with an antifungal drug is a potentially effective treatment that may reduce nephrotoxicity, and perhaps also increase fungicidal activity in patients with systemic candidiasis caused by Candida albicans.

scholarly journals Macrophage-Derived Iron-Bound Lipocalin-2 Correlates with Renal Recovery Markers Following Sepsis-Induced Kidney Damage

2020 ◽  
Vol 21 (20) ◽  
pp. 7527 ◽  
Author(s):  
Christina Mertens ◽  
Laura Kuchler ◽  
Anna Sola ◽  
Roser Guiteras ◽  
Stephan Grein ◽  
...  
Keyword(s):  
Renal Injury ◽  
Cultured Cells ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Renal Recovery ◽  
Iron Loading ◽  
Lipocalin 2 ◽  
Patient Death ◽  
Short Term ◽  
Cellular Source

During the course of sepsis in critically ill patients, kidney dysfunction and damage are among the first events of a complex scenario toward multi-organ failure and patient death. Acute kidney injury triggers the release of lipocalin-2 (Lcn-2), which is involved in both renal injury and recovery. Taking into account that Lcn-2 binds and transports iron with high affinity, we aimed at clarifying if Lcn-2 fulfills different biological functions according to its iron-loading status and its cellular source during sepsis-induced kidney failure. We assessed Lcn-2 levels both in serum and in the supernatant of short-term cultured renal macrophages (MΦ) as well as renal tubular epithelial cells (TEC) isolated from either Sham-operated or cecal ligation and puncture (CLP)-treated septic mice. Total kidney iron content was analyzed by Perls’ staining, while Lcn-2-bound iron in the supernatants of short-term cultured cells was determined by atomic absorption spectroscopy. Lcn-2 protein in serum was rapidly up-regulated at 6 h after sepsis induction and subsequently increased up to 48 h. Lcn-2-levels in the supernatant of TEC peaked at 24 h and were low at 48 h with no change in its iron-loading. In contrast, in renal MΦ Lcn-2 was low at 24 h, but increased at 48 h, where it mainly appeared in its iron-bound form. Whereas TEC-secreted, iron-free Lcn-2 was associated with renal injury, increased MΦ-released iron-bound Lcn-2 was linked to renal recovery. Therefore, we hypothesized that both the cellular source of Lcn-2 as well as its iron-load crucially adds to its biological function during sepsis-induced renal injury.

High Dose Pomegranate Extract Suppresses Neutrophil Myeloperoxidase and Induces Oxidative Stress in a Rat Model of Sepsis

2019 ◽  
Vol 89 (5-6) ◽  
pp. 271-284 ◽  
Author(s):  
Sanaz Tavasoli ◽  
Shahryar Eghtesadi ◽  
Mohamadreza Vafa ◽  
Maziar Moradi-Lakeh ◽  
Alireza Sadeghipour ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Rat Model ◽  
Inflammatory Responses ◽  
Cecal Ligation ◽  
Total Antioxidant Status ◽  
Thiobarbituric Acid ◽  
Pomegranate Juice ◽  
High Dose ◽  
Myeloperoxidase Activity ◽  
Sepsis Induction

Abstract. Introduction: The effect of using high dose pomegranate extract on sepsis and its safety is not clarified. Considering the fact that proper immune and inflammatory responses are needed to cope with infection, the aim of current study was to assess the effect of high dose pomegranate extract consumption on oxidative and inflammatory responses after disease induction in rat model of sepsis. Methods: Sepsis was induced by Cecal Ligation and Perforation (CLP) surgery. Adult male Wistar rats were divided into three groups of eight animals: Sham; CLP and POMx [consumed POMx (250 mg of pomegranate fruit extract/kg/day) for four weeks before CLP]. Results: Peritoneal neutrophil myeloperoxidase activity was significantly lower in POMx compared with Sham and CLP groups ( p < 0.01 and p < 0.05, respectively). Although antioxidant enzymes were higher in POMx group after sepsis induction, lower serum total antioxidant status (TAS) (p < 0.01 compared with both CLP and Sham groups) and higher liver thiobarbituric acid reactive species (TBARS) levels were observed in this group ( p < 0.01 and p < 0.05, compared with Sham and CLP groups, respectively). Conclusion: High dose POMx consumption prior to sepsis induction, suppressed the vital function of neutrophils in early hours after sepsis initiation, resulting in higher oxidative stress. These findings indicate that caution should be made in using high dose pomegranate products. The main message of current study is that such useful compounds as antioxidants including pomegranate juice which have beneficial effects on general health status may have detrimental effects if misused or used in high doses.

scholarly journals The role of adenosine 1a receptor signaling on GFR early after the induction of sepsis

2018 ◽  
Vol 314 (5) ◽  
pp. F788-F797
Author(s):  
Jonathan M. Street ◽  
Erik H. Koritzinsky ◽  
Tiffany R. Bellomo ◽  
Xuzhen Hu ◽  
Peter S. T. Yuen ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Inflammatory Responses ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Cumulative Effect ◽  
Organ Damage ◽  
Tubuloglomerular Feedback ◽  
Organ Injury ◽  
Sodium Reabsorption ◽  
Wild Type

Sepsis and acute kidney injury (AKI) synergistically increase morbidity and mortality in the ICU. How sepsis reduces glomerular filtration rate (GFR) and causes AKI is poorly understood; one proposed mechanism includes tubuloglomerular feedback (TGF). When sodium reabsorption by the proximal tubules is reduced in normal animals, the macula densa senses increased luminal sodium chloride, and then adenosine-1a receptor (A1aR) signaling triggers tubuloglomerular feedback, reducing GFR through afferent arteriole vasoconstriction. We measured GFR and systemic hemodynamics early during cecal ligation and puncture-induced sepsis in wild-type and A1aR-knockout mice. A miniaturized fluorometer was attached to the back of each mouse and recorded the clearance of FITC-sinistrin via transcutaneous fluorescence to monitor GFR. Clinical organ injury markers and cytokines were measured and hemodynamics monitored using implantable transducer telemetry devices. In wild-type mice, GFR was stable within 1 h after surgery, declined by 43% in the next hour, and then fell to less than 10% of baseline after 2 h and 45 min. In contrast, in A1aR-knockout mice GFR was 37% below baseline immediately after surgery and then gradually declined over 4 h. A1aR-knockout mice had similar organ injury and inflammatory responses, albeit with lower heart rate. We conclude that transcutaneous fluorescence can accurately monitor GFR and detect changes rapidly during sepsis. Tubuloglomerular feedback plays a complex role in sepsis; initially, TGF helps maintain GFR in the 1st hour, and over the subsequent 3 h, TGF causes GFR to plummet. By 18 h, TGF has no cumulative effect on renal or extrarenal organ damage.

scholarly journals Melatonin Alleviates Renal Injury in Mouse Model of Sepsis

2021 ◽  
Vol 12 ◽  
Author(s):  
Liyang Chen ◽  
Zhijian Han ◽  
Zhiguang Shi ◽  
Chao Liu ◽  
Qiulun Lu
Keyword(s):  
Renal Injury ◽  
Oxidant Stress ◽  
Mrna Level ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Protective Role ◽  
Cecal Ligation Puncture ◽  
Species Production

Melatonin (N-acetyl-5-methoxytryptamine; MLT) has been shown to have a renal-protective effect against kidney injury. However, the mechanisms underlying the protective role of MLT in sepsis-induced renal injury are yet to be revealed. In this study, MLT alleviated renal dysfunction with the increase of BUN (blood urea nitrogen) and SCR (serum creatinine) and reduction of fibrosis in the CLP (cecal ligation puncture) model. RNA-seq analysis showed that MLT repressed the oxidant stress in response to kidney injury. Our in vitro study showed that MLT suppresses LPS-induced accumulation of ROS (reactive oxygen species) production via SOD2 downregulation and Nox4 upregulation in HK-2 cells. Furthermore, we found that MLT alleviated the inflammatory response, with the mRNA-level reduction of Il-1α, Il-1β, Mcp-1, and Tgf-β1. Taken together, in evaluating the therapeutic effect of MLT on sepsis-induced acute kidney injury, the results showed that MLT alleviated renal damage by regulating the production of ROS.

scholarly journals Urinary Mitochondrial DNA Identifies Renal Dysfunction and Mitochondrial Damage in Sepsis-Induced Acute Kidney Injury

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Qiongyuan Hu ◽  
Jianan Ren ◽  
Huajian Ren ◽  
Jie Wu ◽  
Xiuwen Wu ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Mitochondrial Dna ◽  
Mitochondrial Dysfunction ◽  
Renal Dysfunction ◽  
Renal Injury ◽  
Cecal Ligation ◽  
Surrogate Marker ◽  
Kidney Injury ◽  
Plasma Creatinine ◽  
Acute Renal Dysfunction

Background. Recent animal studies have shown that mitochondrial dysfunction initiates and accelerates renal injury in sepsis, but its role in sepsis remains unknown. Mitochondrial stress or dying cells can lead to fragmentation of the mitochondrial genome, which is considered a surrogate marker of mitochondrial dysfunction. Therefore, we evaluated the efficiency of urinary mitochondrial DNA (UmtDNA) as a marker of renal dysfunction during sepsis-induced acute kidney injury (AKI). Methods. We isolated DNA from plasma and urine of patients. mtDNA levels were quantified by quantitative PCR. Sepsis patients were divided into no AKI, mild AKI, and severe AKI groups according to RIFLE criteria. Additionally, cecal ligation and puncture (CLP) was established in rats to evaluate the association between UmtDNA and mitochondrial function. Results. A total of 52 (49.5%) developed AKI among enrolled sepsis patients. Increased systemic mtDNA did not correlate with systemic inflammation or acute renal dysfunction in sepsis patients, while AKI did not have an additional effect on circulating mtDNA levels. In contrast, UmtDNA was significantly enriched in severe AKI patients compared with that in the mild AKI or no AKI group, positively correlated with plasma creatinine, urinary neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1, and inversely with the estimated glomerular filtration rate. Additionally, UmtDNA increased in rats following CLP-induced sepsis. UmtDNA was predictive of AKI development and correlated with plasma creatinine and blood urea nitrogen in the rat sepsis model. Finally, the UmtDNA level was inversely correlated with the cortical mtDNA copy number and relative expression of mitochondrial gene in the kidney. Conclusion. An elevated UmtDNA level correlates with mitochondrial dysfunction and renal injury in sepsis patients, indicating renal mitochondrial injury induced by sepsis. Therefore, UmtDNA may be regarded as a valuable biomarker for the occurrence of AKI and the development of mitochondria-targeted therapies following sepsis-induced AKI.

scholarly journals Urinary proteome of dogs with kidney injury during babesiosis

2019 ◽  
Author(s):  
Dagmara Winiarczyk ◽  
Katarzyna Michalak ◽  
Łukasz Adaszek ◽  
Mateusz Winiarczyk ◽  
Stanisław Winiarczyk
Keyword(s):  
Acute Kidney Injury ◽  
Renal Injury ◽  
Metabolic Pathways ◽  
Inflammatory Responses ◽  
Kidney Injury ◽  
Urine Samples ◽  
Characteristic Analysis ◽  
Mesenchymal Transition ◽  
Healthy Dogs ◽  
Potential Biomarkers

Abstract Background Acute kidney injury is the most frequent complication of babesiosis in dogs and may provide a natural model for identifying early and specific markers of kidney injury in this species. There are limited data on urine proteomics in dogs, and none of the effect of babesiosis on the urine proteome. This study aimed to identify urinary proteins of dogs with kidney injury during the natural course of babesiosis caused by Babesia canis, and to compare them with proteins in a control group to reveal any potential biomarkers predicting renal injury before the presence of azotemia. Urine samples were collected from 10 dogs of various breeds and sex with naturally occurring babesiosis, and 10 healthy dogs. Pooled urine samples from both groups were separated by 2D (two-dimensional) electrophoresis, followed by protein identification using MALDI-TOF (matrix-assisted laser desorption ionization time of flight) mass spectrometry. Results In total, 176 proteins were identified in the urine samples from healthy dogs, and 403 proteins were identified in the urine samples from dogs with babesiosis. Of the 176 proteins, 146 were assigned exclusively to healthy dogs, and 373 of the 403 proteins were assigned exclusively to dogs with babesiosis; 30 proteins were common for both groups. Characteristic analysis of 373 proteins found in dogs with babesiosis led to the isolation of 8 proteins associated with 10 metabolic pathways involved in immune and inflammatory responses. Conclusions It was hypothesized that epithelial-mesenchymal transition might play an important role in the mechanisms underlying pathological changes in renal tissue during babesiosis, as indicated by a causal relationship network built by combining 5 of the 10 selected metabolic pathways, and 4 of the 8 proteins associated with these pathways; this network included cadherins, gonadotropin releasing hormone receptors, inflammatory responses mediated by chemokine and cytokine signalling pathways, integrins, interleukins, and TGF-β (transforming growth factor β) pathways. Those pathways were linked by interleukin-13, bone morphogenetic protein 7, α2(1) collagen, and tyrosine protein kinase Fer, which are potential biomarkers of damage during babesiosis in dogs, that might indicate early renal injury. Keywords: Acute kidney injury, Babesiosis, Dog, Proteomics, Urine

scholarly journals The Effect of Mannitol Addition on Hydration in Acute Kidney Injury Event After High Dose Cisplatin Chemotherapy: An Ambispective Cohort Study

2021 ◽  
Author(s):  
Andhika Rachman ◽  
Syahidatul Wafa ◽  
Pringgodigdo Nugroho ◽  
Sukamto Koesnoe
Keyword(s):  
Acute Kidney Injury ◽  
Cohort Study ◽  
Risk Ratio ◽  
Renal Injury ◽  
Kidney Injury ◽  
Bivariate Analysis ◽  
P Value ◽  
High Dose ◽  
Adjusted Risk ◽  
Injury Event

Abstract Background: Saline hydration with addition of mannitol have commonly being strategy to avoid cisplatin induced acute kidney injury. While the initial reports demonstrated that mannitol diuresis decreased cisplatin induced renal injury, others have shown renal injury to be worsened.Objective: To compare the risk of acute kidney injury in cancer patients receiving high dose cisplatin with addition and without addition of mannitol.Method: This was an ambispective cohort study based on consecutive sampling at Cipto Mangunkusumo General Hospital and Mochtar Riady Comprehensive Cancer Centre (MRCCC) Siloam Hospitals. The data was obtained from September 2017 to February 2018. The choice of mannitol administration based on responsible physician clinical judgement. The outcome was any increment more than 0,3 mg/dl or 1,5 times from baseline of serum creatinine. Analysis was done by using SPSS statistic for univariate, bivariate and multivariate logistic regression to obtain crude risk ratio and adjusted risk ratio of cisplatin induced acute kidney injury probability of mannitol addition on hydration.Result: Data from 110 patients (57,3% male) with a median age of 44,5 years (range 19 to 60 years) were collected; 47 received saline alone and 63 received saline with addition of mannitol. Acute kidney injury were higher in mannitol vs non mannitol group. Bivariate analysis showed higher probability of post chemotherapy AKI in mannitol group (RR 2,168; 95% CI 0,839-5,6). On multivariate analysis the adjusted RR was 3,52 (95% CI 1,11-11,162; p value = 0,033) by controlling age.Conclusion: The addition of mannitol on hydration had higher risk of AKI after high dose cisplatin chemotherapy.

Low-dose carvedilol protects against acute septic renal injury in rats during the early and late phases

2015 ◽  
Vol 93 (6) ◽  
pp. 443-450 ◽  
Author(s):  
Hala Salah Abdel kawy
Keyword(s):  
Renal Injury ◽  
Cecal Ligation ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Kidney Injury ◽  
Serum Levels ◽  
Renal Perfusion ◽  
Protein Carbonyls ◽  
Necrosis Factor Alpha ◽  
Inflammatory Parameters ◽  
The Impact

Recent findings from septic acute renal injury studies have implicated the mitochondrion as an important factor in kidney injury, and that increased sympathetic nerve activity may contribute to the induction of organ failure. This study investigated the impact of a nondepressor dose of carvedilol, which is a beta-adrenoreceptor antagonist with antioxidant activity, on septic renal injury induced in rats with cecal ligation and puncture (CLP). Three groups of rats were studied. The first group was the sham-operated control. The other 2 groups of rats underwent CLP, and were administered either the vehicle or carvedilol (2.0 mg/kg body mass, by intraperitoneal (i.p.) injection, daily for 2 days as well as 30 min prior to CLP). Kidney function, inflammatory parameters, mitochondrial function, and renal perfusion pressure (RPP) were investigated at 6 and 18 h after CLP. Carvedilol did not significantly induce hypotension, and it significantly improved RPP and renal dysfunction induced with CLP, together with significant reductions in serum levels of interleukin 6 and tumor necrosis factor-alpha. Septic kidney injury mediated increased levels of malondialdehyde and protein carbonyls. Carvedilol also attenuated the decrease in kidney mitochondrial glutathione and nicotinamide adenine dinucleotide phosphate dehydrogenase. Further, intracellular renal edema and inflammation induced with CLP were reduced with carvedilol. These findings suggest renoprotective effects of carvedilol in sepsis.

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