scholarly journals (Mesenchymal) Stem Cell-Based Therapy in Cisplatin-Induced Acute Kidney Injury Animal Model: Risk of Immunogenicity and Tumorigenicity

2017 ◽  
Vol 2017 ◽  
pp. 1-17 ◽  
Author(s):  
Ž. Večerić-Haler ◽  
A. Cerar ◽  
M. Perše
Keyword(s):  
Immune Response ◽  
Acute Kidney Injury ◽  
Animal Models ◽  
Animal Studies ◽  
Therapeutic Strategy ◽  
Kidney Injury ◽  
The Body ◽  
Model Risk ◽  
Cisplatin Nephrotoxicity ◽  
Cell Based Therapy

Pathogenesis of AKI is complex and involves both local events in the kidney as well as systemic effects in the body that are interconnected and interdependent. Despite intensive investigations there is still no pharmacological agent that could provide complete protection against cisplatin nephrotoxicity. In the last decade mesenchymal stem cells (MSCs) have been proposed as a potentially useful therapeutic strategy in various diseases, including acute kidney injury. Although MSCs have potent immunosuppressive properties, animal studies also suggest that transplanted MSCs may elicit immune response. Interestingly, tumorigenicity of transplanted MSCs in animal studies has been rarely studied. Since the risk of tumorigenicity of particular therapy as well as the immune response to solid or cell grafts is a major issue in clinical trials, the aim of the present paper is to critically summarize the results of MSC transplantation on animal models of AKI, particularly cisplatin-induced animal models, and to expose results and main concerns about immunogenicity and tumorigenicity of transplanted MSCs, two important issues that need to be addressed in future studies.

scholarly journals P0517RENAL STEM CELLS (ARPCS) AS A NEPHROPROTECTIVE APPROACH DURING CISPLATIN-INDUCED ACUTE KIDNEY INJURY: A DEFENSE MECHANISM BY EXTRACELLULAR VESICLES CARRYING THE CYP1B1 GENE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
ROSSANA FRANZIN ◽  
Fabio Sallustio ◽  
Claudia Curci ◽  
Simona Simone ◽  
Angela Picerno ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Kidney Injury ◽  
Extracellular Vesicles ◽  
Caspase 3 ◽  
Defense Mechanism ◽  
Kidney Injury ◽  
The Body ◽  
Cell Culture Supernatant ◽  
Protective Agent ◽  
Cyp1b1 Gene

Abstract Background and Aims Cisplatin, is a nonspecific cytotoxic agent that primarily interferes with cellular DNA replication and the cell cycle, nevertheless it lacks tumor selectivity and acts also in normal cells. The most serious adverse reaction of cisplatin is Acute Kidney Injury (AKI), limiting its use and efficacy in chemotherapy. Cisplatin nephrotoxicity is observed in more than 30% of older patients, however the mechanism of nephrotoxicity remains unclear and specific preventive measures are not available. Today, there is an urgent need for specific nephroprotective strategies to be used during cisplatin chemotherapy. Recently, we found that tubular stem/progenitor cells (tARPC) are able to protect the tubular epithelial (RPTEC) from cisplatin induced injury, preserving their proliferation and inhibiting apoptosis. The aim of this study was to identify the molecular mechanisms involved in tARPC-mediated resistance to cisplatin. Method Co-cultures of RPTEC cells and tARPCs were exposed to cisplatin (2.5 µM) for 6 h and then kept in culture for 96 h. Gene expression profile was obtained from tARPCs and RPTECs by Agilent SurePrint G3 Human Gene Expression Microarrays. Genespring and R software were used for the analysis. Gene expression data were validated by Real-time PCR. Extracellular vesicles were isolated from cell culture supernatant by miRCURY Exosome Cell/Urine/CSF Kit (Qiagen) and RNA contained in extracellular vesicles was purified, analyzed in quality by Bioanalyzer (RNA nano) and evaluated by qPCR. The BrdU assay and caspase 3 were used to measure proliferation and apoptosis levels. Immunohistochemical expression of activated caspase-3 was used as a marker of apoptosis in RPTECs. Results By a whole-genome gene expression analysis, we found 107 genes specifically modulated by RPTECs in response to cisplatin and, among these, 30 genes induced by ARPCs following the cisplatin damage. In particular, we found a strong upregulation of the CYP1B1 gene (false discovery rate corrected p value <0.05; fold change=4,1). The qPCR confirmed the increase in CYP1B1 levels in the co-cultures with respect to the respective basal conditions (p <0.05). Interestingly, the CYP1B1 mRNA was also enveloped in Extracellular Vesicles released in the cell co-culture media by tARPC and RPTEC after cisplatin exposition. The CYP1B1 gene encodes a member of the cytochrome P450 superfamily of enzymes and the produced enzyme metabolizes procarcinogens, such as polycyclic aromatic hydrocarbons. CYP1B1 has been shown to be active within tumors and is also capable of metabolizing a structurally diverse range of anticancer drugs. It is responsible for the resistance to docetaxel, cisplatin, tamoxifen and nucleoside analogues. CYP1B1 is involved in the detoxification of the body by various exogenous toxic agents, including cisplatin. We found that CYP1B1 gene was expressed at low levels in RPTECs and in cisplatin-damaged RPTECs. Moreover, 96 h days after 2.5 μM exposure to cisplatin, RPTECs reduced the proliferation and underwent in apoptosis, as showed by caspase 3. However, in co-culture with ARPCs, ARPC cellular and extracellular vesicles CYP1B1 gene expression significantly increased, the apoptotic process was stopped and RPTECs increased their proliferation rate. These data support the hypothesis that ARPCs are sensor of cisplatin damaged-RPTEC and confers cisplatin resistance by transferring CYP1B1 gene in extracellular vesicles. Conclusion This is the first evidence of a cisplatin-induced overexpression of CYP1b1 in renal epithelial cells as a defense mechanism against cisplatin toxicity. This is consistent with our previous data showing that renal progenitors are resistant to cisplatin. The findings may have biological and clinical significance in terms of their implications in cellular communications and potential use of CYP1B1 as biomarkers for AKI induced by cisplatin or as protective agent.

scholarly journals Peptide hormone relaxin: from bench to bedside

2018 ◽  
Vol 314 (6) ◽  
pp. R753-R760 ◽  
Author(s):  
Maria Jelinic ◽  
Sarah A. Marshall ◽  
Dennis Stewart ◽  
Elaine Unemori ◽  
Laura J. Parry ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Animal Models ◽  
Animal Studies ◽  
Ischemia Reperfusion ◽  
Peptide Hormone ◽  
The Body ◽  
Cervical Ripening ◽  
Matrix Remodeling ◽  
Vitro Fertilization

The peptide hormone relaxin has numerous roles both within and independent of pregnancy and is often thought of as a “pleiotropic hormone.” Relaxin targets several tissues throughout the body, and has many functions associated with extracellular matrix remodeling and the vasculature. This review considers the potential therapeutic applications of relaxin in cervical ripening, in vitro fertilization, preeclampsia, acute heart failure, ischemia-reperfusion, and cirrhosis. We first outline the animal models used in preclinical studies to progress relaxin into clinical trials and then discuss the findings from these studies. In many cases, the positive outcomes from preclinical animal studies were not replicated in human clinical trials. Therefore, the focus of this review is to evaluate the various animal models used to develop relaxin as a potential therapeutic and consider the limitations that must be addressed in future studies. These include the use of human relaxin in animals, duration of relaxin treatment, and the appropriateness of the clinical conditions being considered for relaxin therapy.

scholarly journals Remote Ischemic Preconditioning Protects Cisplatin-Induced Acute Kidney Injury through the PTEN/AKT Signaling Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Wanfen Zhang ◽  
Cheng Chen ◽  
Ran Jing ◽  
Tongqiang Liu ◽  
Bicheng Liu
Keyword(s):  
Acute Kidney Injury ◽  
Ischemic Preconditioning ◽  
Therapeutic Strategy ◽  
Molecular Mechanisms ◽  
Kidney Injury ◽  
Akt Signaling ◽  
Remote Ischemic Preconditioning ◽  
Pten Mrna ◽  
Induce Resistance ◽  
In Cis

Although cisplatin (Cis) is an effective chemotherapeutic agent in treatment of various cancers, its adverse effect of nephrotoxicity limits the clinical application. Remote ischemic preconditioning (RIPC) is a strategy to induce resistance in a target organ against the oxidative stress and injury by applying transient, brief episodes of ischemia. However, whether RIPC exerts protective effect on Cis-induced renal injury remains unclear. In this study, we showed that RIPC significantly alleviated the renal functional and histopathological damage of Cis-induced acute kidney injury (AKI) mice. Furthermore, RIPC substantially reversed the downregulation of miR-144 and upregulation of PTEN in renal tissues of Cis-induced AKI mice and alleviated tubular cell apoptosis via activating PTEN/AKT signaling. In mechanism, we demonstrated that miR-144 directly targets the 3’-UTR of PTEN mRNA, and then the elevation of miR-144 in RIPC activates PTEN/AKT signaling by downregulating PTEN expression to achieve its antiapoptosis effect. Collectively, our results indicate that RIPC may be a potential therapeutic strategy in Cis-induced AKI, and provide insights on the underlying molecular mechanisms of cisplatin’s nephrotoxicity.

scholarly journals Protective Effects of Recombinant Human Soluble Thrombomodulin on Lipopolysaccharide-Induced Acute Kidney Injury

2020 ◽  
Vol 21 (7) ◽  
pp. 2519
Author(s):  
Yuji Nozaki ◽  
Jinhai Ri ◽  
Kenji Sakai ◽  
Kaoru Niki ◽  
Masanori Funauchi ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Renal Damage ◽  
Cell Activation ◽  
Therapeutic Strategy ◽  
Cytokine Production ◽  
Kidney Injury ◽  
Protective Effects ◽  
Inflammatory Cytokine Production ◽  
Soluble Thrombomodulin ◽  
Anticoagulant Function

Thrombomodulin (TM) is a single transmembrane, multidomain glycoprotein receptor for thrombin, and is best known for its role as a cofactor in a clinically important natural anticoagulant pathway. In addition to its anticoagulant function, TM has well-defined anti-inflammatory properties. Soluble TM levels increase significantly in the plasma of septic patients; however, the possible involvement of recombinant human soluble TM (rTM) transduction in the pathogenesis of lipopolysaccharide (LPS)-induced nephrotoxicity, including acute kidney injury (AKI), has remained unclear. Mice were injected intraperitoneally with 15 mg/kg LPS. rTM (3 mg/kg) or saline was administered to the animals before the 3 and 24 h LPS-injection. At 24 and 48 h, blood urea nitrogen, the inflammatory cytokines in sera and kidney, and histological findings were assessed. Cell activation and apoptosis signal was assessed by Western blot analysis. In this study using a mouse model of LPS-induced AKI, we found that rTM attenuated renal damage by reducing both cytokine and cell activation and apoptosis signals with the accumulation of CD4+ T-cells, CD11c+ cells, and F4/80+ cells via phospho c-Jun activations and Bax expression. These findings suggest that the mechanism underlying these effects of TM may be mediated by a reduction in inflammatory cytokine production in response to LPS. These molecules might thereby provide a new therapeutic strategy in the context of AKI with sepsis.

scholarly journals Bridging translation for acute kidney injury with better preclinical modeling of human disease

2016 ◽  
Vol 310 (10) ◽  
pp. F972-F984 ◽  
Author(s):  
Nataliya I. Skrypnyk ◽  
Leah J. Siskind ◽  
Sarah Faubel ◽  
Mark P. de Caestecker
Keyword(s):  
Acute Kidney Injury ◽  
Animal Studies ◽  
Kidney Injury ◽  
Clinical Problem ◽  
Molecular Classification ◽  
Preclinical Models ◽  
Medical Need ◽  
Intervention Trials

The current lack of effective therapeutics for patients with acute kidney injury (AKI) represents an important and unmet medical need. Given the importance of the clinical problem, it is time for us to take a few steps back and reexamine current practices. The focus of this review is to explore the extent to which failure of therapeutic translation from animal studies to human studies stems from deficiencies in the preclinical models of AKI. We will evaluate whether the preclinical models of AKI that are commonly used recapitulate the known pathophysiologies of AKI that are being modeled in humans, focusing on four common scenarios that are studied in clinical therapeutic intervention trials: cardiac surgery-induced AKI; contrast-induced AKI; cisplatin-induced AKI; and sepsis associated AKI. Based on our observations, we have identified a number of common limitations in current preclinical modeling of AKI that could be addressed. In the long term, we suggest that progress in developing better preclinical models of AKI will depend on developing a better understanding of human AKI. To this this end, we suggest that there is a need to develop greater in-depth molecular analyses of kidney biopsy tissues coupled with improved clinical and molecular classification of patients with AKI.

scholarly journals Comparison of 99mTc-DMSA renal scintigraphy with biochemical and histopathological findings in animal models of acute kidney injury

2017 ◽  
Vol 434 (1-2) ◽  
pp. 163-169 ◽  
Author(s):  
Hossein Fatemikia ◽  
Mohammad Seyedabadi ◽  
Zynab Karimi ◽  
Kiarash Tanha ◽  
Majid Assadi ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Animal Models ◽  
Kidney Injury ◽  
Renal Scintigraphy ◽  
Histopathological Findings

scholarly journals Cul4a attenuates LPS-induced acute kidney injury via blocking NF-κB signaling pathway in sepsis

2021 ◽  
Author(s):  
Jing Zhao ◽  
Qiuxia Duan ◽  
Cuihong Dong ◽  
Jing Cui
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Animal Models ◽  
Protective Factor ◽  
Kidney Injury ◽  
Inflammatory Factors ◽  
Common Disease ◽  
Protective Function ◽  
Apoptosis And Inflammation ◽  
End Stage

Background: Acute kidney injury (AKI) is a common disease that can develop into end-stage kidney disease. Sepsis is one of the main causes of AKI. Currently, there is no satisfactory way to treat septic AKI. Therefore, we have shown the protective function of Cul4a in septic AKI and its molecular mechanism. Methods: The cellular and animal models of septic AKI were established by using lipopolysaccharide (LPS). Western blot (WB) was employed to analyze Cul4a expression. RT-qPCR was employed to test the expression of Cul4a, SOD1, SOD2, GPX1, CAT, IL-6, TNF-α, Bcl-2, IL-1β, Bax and KIM-1 mRNA. ELISA was performed to detect the contents of inflammatory factors and LDH. CCK-8 was utilized to detect the cell viability. Flow cytometry was utilized to analyze the apoptosis. DHE-ROS kit was used to detect the content of ROS. Results: Cul4a was down-regulated in cellular and animal models of septic AKI. Oxidative stress is obviously induced by LPS, as well as apoptosis and inflammation. However, these can be significantly inhibited by up-regulating Cul4a. Moreover, LPS induced the activation of the NF-κB pathway, which could also be inhibited by overexpression of Cul4a. Conclusion: Cul4a was found to be a protective factor in septic AKI, which could inhibit LPS-induced oxidative stress, apoptosis and inflammation of HK-2 cells by inhibiting NF-κB pathway.

scholarly journals Elevated serum galectin-1 concentrations are associated with increased risks of mortality and acute kidney injury in critically ill patients

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0257558
Author(s):  
Ruey-Hsing Chou ◽  
Chuan-Tsai Tsai ◽  
Ya-Wen Lu ◽  
Jiun-Yu Guo ◽  
Chi-Ting Lu ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Critically Ill ◽  
Sofa Score ◽  
Critically Ill Patients ◽  
Medical Center ◽  
Elevated Serum ◽  
Kidney Injury ◽  
The Body ◽  
Icu Admission ◽  
Increased Risk

Background Galectin-1 (Gal-1), a member of the β-galactoside binding protein family, is associated with inflammation and chronic kidney disease. However, the effect of Gal-1 on mortality and acute kidney injury (AKI) in critically-ill patients remain unclear. Methods From May 2018 to March 2020, 350 patients admitted to the medical intensive care unit (ICU) of Taipei Veterans General Hospital, a tertiary medical center, were enrolled in this study. Forty-one patients receiving long-term renal replacement therapy were excluded. Serum Gal-1 levels were determined within 24 h of ICU admission. The patients were divided into tertiles according to their serum Gal-1 levels (low, serum Gal-1 < 39 ng/ml; median, 39–70 ng/ml; high, ≥71 ng/ml). All patients were followed for 90 days or until death. Results Mortality in the ICU and at 90 days was greater among patients with elevated serum Gal-1 levels. In analyses adjusted for the body mass index, malignancy, sepsis, Sequential Organ Failure Assessment (SOFA) score, and serum lactate level, the serum Gal-1 level remained an independent predictor of 90-day mortality [median vs. low: adjusted hazard ratio (aHR) 2.11, 95% confidence interval (CI) 1.24–3.60, p = 0.006; high vs. low: aHR 3.21, 95% CI 1.90–5.42, p < 0.001]. Higher serum Gal-1 levels were also associated with a higher incidence of AKI within 48 h after ICU admission, independent of the SOFA score and renal function (median vs. low: aHR 2.77, 95% CI 1.21–6.34, p = 0.016; high vs. low: aHR 2.88, 95% CI 1.20–6.88, p = 0.017). The results were consistent among different subgroups with high and low Gal-1 levels. Conclusion Serum Gal-1 elevation at the time of ICU admission were associated with an increased risk of mortality at 90 days, and an increased incidence of AKI within 48 h after ICU admission.

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