scholarly journals Prevention of contrast-induced nephropathy by limb ischemic preconditioning: underlying mechanisms and clinical effects

2018 ◽  
Vol 314 (3) ◽  
pp. F319-F328 ◽  
Author(s):  
George J. Dugbartey ◽  
Andrew N. Redington
Keyword(s):  
Ischemic Preconditioning ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Coronary Intervention ◽  
Experimental Models ◽  
Clinical Effects ◽  
Renal Protection ◽  
Contrast Induced Nephropathy ◽  
Iodinated Contrast

Contrast-induced nephropathy (CIN) is an important complication following diagnostic radiographic imaging and interventional therapy. It results from administration of intravascular iodinated contrast media (CM) and is currently the third most common cause of hospital-acquired acute kidney injury. CIN is associated with increased morbidity, prolonged hospitalization, and higher mortality. Although the importance of CIN is widely appreciated, and its occurrence can be mitigated by the use of pre- and posthydration protocols and low osmolar instead of high osmolar iodine-containing CM, specific prophylactic therapy is lacking. Remote ischemic preconditioning (RIPC), induced through short cycles of ischemia-reperfusion applied to the limb, is an intriguing new strategy that has been shown to reduce myocardial infarction size in patients undergoing emergency percutaneous coronary intervention. Furthermore, multiple proof-of-principle clinical studies have suggested benefit in several other ischemia-reperfusion syndromes, including stroke. Perhaps somewhat surprisingly, RIPC also is emerging as a promising strategy for CIN prevention. In this review, we discuss current clinical and experimental developments regarding the biology of CIN, concentrating on the pathophysiology of CIN, and cellular and molecular mechanisms by which limb ischemic preconditioning may confer renal protection in clinical and experimental models of CIN.

scholarly journals Effect of Remote Ischemic Preconditioning on Perioperative Cardiac Events in Patients Undergoing Elective Percutaneous Coronary Intervention: A Meta-Analysis of 16 Randomized Trials

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Xiangming Wang ◽  
Na Kong ◽  
Chuanwei Zhou ◽  
Deeraj Mungun ◽  
Zakaria Iyan ◽  
...  
Keyword(s):  
Ischemic Preconditioning ◽  
Meta Analysis ◽  
Kidney Injury ◽  
Coronary Intervention ◽  
Remote Ischemic Preconditioning ◽  
Cochrane Library ◽  
Control Group ◽  
Cardiac Events ◽  
Renal Protection ◽  
Elective Percutaneous Coronary Intervention

Background. The main objective of this meta-analysis was to investigate whether remote ischemic preconditioning (RIPC) reduces cardiac and renal events in patients undergoing elective cardiovascular interventions. Methods and Results. We systematically searched articles published from 2006 to 2016 in PubMed, EMBASE, Web of Science, Cochrane Library, and Google Scholar. Odds ratios (ORs) with 95% confidence intervals (CIs) were used as the effect index for dichotomous variables. The standardized mean differences (SMDs) with 95% CIs were calculated as the pooled continuous effect. Sixteen RCTs of 2435 patients undergoing elective PCI were selected. Compared with control group, RIPC could significantly reduce the incidence of perioperative myocardial infarction (OR = 0.64; 95% CI: 0.48–0.86; P=0.003) and acute kidney injury (OR = 0.56; 95% CI: 0.322–0.99; P=0.049). Metaregression analysis showed that the reduction of PMI by RIPC was enhanced for CAD patients with multivessel disease (coef.: −0.05 [-0.09;-0.01], P=0.022). There were no differences in the changes of cTnI (P=0.934) and CRP (P=0.075) in two groups. Conclusion. Our meta-analysis of RCTs demonstrated that RIPC can provide cardiac and renal protection for patients undergoing elective PCI, while no beneficial effect on reducing the levels of cTnI and CRP after PCI was reported.

scholarly journals Determination of a microRNA signature of protective kidney ischemic preconditioning originating from proximal tubules

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Usman Khalid ◽  
Robert H. Jenkins ◽  
Robert Andrews ◽  
Gilda Pino-Chavez ◽  
Benjamin C. Cossins ◽  
...  
Keyword(s):  
Ischemic Preconditioning ◽  
Ischemia Reperfusion Injury ◽  
Rat Kidney ◽  
Ischemia Reperfusion ◽  
Repetitive Sequences ◽  
Kidney Injury ◽  
Dose Dependence ◽  
Experimental Models ◽  
Proximal Tubules ◽  
Microrna Sequencing

AbstractIschemic preconditioning (IPC) is effective in limiting subsequent ischemic acute kidney injury in experimental models. MicroRNAs are an important class of post-transcriptional regulator and show promise as biomarkers of kidney injury. We evaluated the time- and dose-dependence of benefit from IPC in a rat model of functional (bilateral) ischemia–reperfusion injury (IRI). We found optimal protection from subsequent injury following short, repetitive sequences of preconditioning insult. We subsequently used hybridization array and microRNA sequencing to characterize microRNA signatures of protective IPC and of IRI. These approaches identified a profile of microRNA changes consequent on IRI, that were limited by prior IPC. To localize these signals within the kidney, we used laser capture microdissection and RT-qPCR to measure microRNA abundance in nephron segments, pinpointing microRNA changes principally to glomeruli and proximal tubules. Our data describe a unique microRNA signature for IRI in the rat kidney. Pulsatile IPC reduces kidney damage following IRI and diminishes this microRNA signal. We have also identified candidate microRNAs that may act as biomarkers of injury and therapeutic targets in this context.

scholarly journals miR-182-5p and miR-378a-3p regulate ferroptosis in I/R-induced renal injury

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Chenguang Ding ◽  
Xiaoming Ding ◽  
Jin Zheng ◽  
Bo Wang ◽  
Yang Li ◽  
...  
Keyword(s):  
Cell Death ◽  
Renal Injury ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Luciferase Reporter ◽  
Renal Tubular Cell ◽  
In Cells

Abstract Renal tubular cell death is the key factor of the pathogenesis of ischemia/reperfusion (I/R) kidney injury. Ferroptosis is a type of regulated cell death (RCD) found in various diseases. However, the underlying molecular mechanisms related to ferroptosis in renal I/R injury remain unclear. In the present study, we investigated the regulatory role of microRNAs on ferroptosis in I/R-induced renal injury. We established the I/R-induced renal injury model in rats, and H/R induced HK-2 cells injury in vitro. CCK-8 was used to measure cell viability. Fe2+ and ROS levels were assayed to evaluate the activation of ferroptosis. We performed RNA sequencing to profile the miRNAs expression in H/R-induced injury and ferroptosis. Western blot analysis was used to detect the protein expression. qRT-PCR was used to detect the mRNA and miRNA levels in cells and tissues. We further used luciferase reporter assay to verify the direct targeting effect of miRNA. We found that ischemia/reperfusion-induced ferroptosis in rat’s kidney. We identified that miR-182-5p and miR-378a-3p were upregulated in the ferroptosis and H/R-induced injury, and correlates reversely with glutathione peroxidases 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) expression in renal I/R injury tissues, respectively. In vitro studies showed that miR-182-5p and miR-378a-3p induced ferroptosis in cells. We further found that miR-182-5p and miR-378a-3p regulated the expression of GPX4 and SLC7A11 negatively by directly binding to the 3′UTR of GPX4 and SLC7A11 mRNA. In vivo study showed that silencing miR-182-5p and miR-378a-3p alleviated the I/R-induced renal injury in rats. In conclusion, we demonstrated that I/R induced upregulation of miR-182-5p and miR-378a-3p, leading to activation of ferroptosis in renal injury through downregulation of GPX4 and SLC7A11.

Superagonistic CD28 Protects against Renal Ischemic Injury by Expansion of Regulatory T-Cell

2017 ◽  
Vol 45 (5) ◽  
pp. 389-399 ◽  
Author(s):  
Yiran Liang ◽  
Yan Li ◽  
Qing Kuang ◽  
Xiaoqiang Ding ◽  
Zheng Wei ◽  
...  
Keyword(s):  
T Cell ◽  
Peripheral Blood ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Ischemic Precondition ◽  
Cell Receptor ◽  
Treg Cells ◽  
Tubular Damage ◽  
Renal Protection

Background: Regulatory T (Treg) cells are a highly suppressive subset of CD4+ lymphocytes and have recently been proved to be crucial to suppress the inflammatory responses of ischemic kidney injury. CD28 superagonists (CD28sa) are monoclonal antibodies that preferentially expand Treg cells without a T-cell receptor and a costimulatory signal. This study aims to test the protection and discover the mechanisms of CD28sa treatment against renal ischemia-reperfusion (IR) injury (IRI). Methods: Male C57BL/6N mice were treated with CD28sa via peritoneal injection (0.1 mg) 6 days before the induction of IRI, or with 18-min ischemic precondition (IPC). IRI was induced by bilateral clamping of renal pedicles for 35 min followed by reperfusion. The role of Treg expansion in renal protection conferred by CD28sa treatment was examined using anti-CD25 antibody. Results: CD28sa treatment alone significantly increased the percentage of Treg cells in the spleen (18.10 ± 2.00 vs. 6.64 ± 0.86%, p < 0.01), peripheral blood (16.43 ± 5.94 vs. 2.57 ± 1.09%, p < 0.01), and kidney (2.69 ± 0.90 vs. 0.53 ± 0.14%, p < 0.01) of C57BL/6N mice 6 days after the administration. Mice pretreated with CD28sa or IPC had less renal injury at 24 h after IRI with attenuation of renal tubular damage and lower serum creatinine compared with the mice that underwent renal IRI alone. The number of infiltrating macrophages in the kidney and IFN-γ secreting CD4+ T cells in peripheral blood were diminished in the CD28sa-IR group and the IPC-IR group. The renal protection bestowed by CD28sa or IPC was abolished by anti-CD25 antibody administration. Conclusions: Treg expansion induced by CD28sa ameliorated renal IRI.

scholarly journals Normothermic Ex-vivo Kidney Perfusion in a Porcine Auto-Transplantation Model Preserves the Expression of Key Mitochondrial Proteins: An Unbiased Proteomics Analysis

2020 ◽  
Author(s):  
Caitriona M. McEvoy ◽  
Sergi Clotet-Freixas ◽  
Tomas Tokar ◽  
Chiara Pastrello ◽  
Shelby Reid ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Graft Function ◽  
Kidney Injury ◽  
Tca Cycle ◽  
Proteomics Analysis ◽  
Beneficial Effects ◽  
Kidney Perfusion

AbstractNormothermic ex-vivo kidney perfusion (NEVKP) results in significantly improved graft function in porcine auto-transplant models of DCD injury compared to static cold storage (SCS); however, the molecular mechanisms underlying these beneficial effects remain unclear. We performed an unbiased proteomics analysis of 28 kidney biopsies obtained at 3 time points from pig kidneys subjected to 30-minutes of warm ischemia, followed by 8 hours of NEVKP or SCS, and auto-transplantation. 70/6593 proteins quantified were differentially expressed between NEVKP and SCS groups (FDR<0.05). Proteins increased in NEVKP mediated key metabolic processes including fatty acid ß-oxidation, the TCA-cycle and oxidative phosphorylation. Comparison of our findings with external datasets of ischemia-reperfusion, and other models of kidney injury confirmed that 47 of our proteins represent a common signature of kidney injury reversed or attenuated by NEVKP. We validated key metabolic proteins (ETFB, CPT2) by immunoblotting. Transcription factor databases identified PPARGC1A, PPARA/G/D and RXRA/B as the upstream regulators of our dataset, and we confirmed their increased expression in NEVKP with RT-PCR. The proteome-level changes observed in NEVKP mediate critical metabolic pathways that may explain the improved graft function observed. These effects may be coordinated by PPAR-family transcription factors, and may represent novel therapeutic targets in ischemia-reperfusion injury.

Abstract 655: Ischemia-induced Epoxyeicosatrienoic Acid Release Protects Female Rats From Acute Kidney Injury

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Duska Dragun ◽  
Uwe Hoff ◽  
Maximilian Blum ◽  
Gordana Bubalo ◽  
Mandy Fechner ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Creatinine Clearance ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Female Rats ◽  
Epoxyeicosatrienoic Acid ◽  
Renal Protection ◽  
Sham Control ◽  
Male And Female ◽  
Enhanced Production

Females are naturally protected against ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) in various clinical and experimental settings. However, the underlying mechanisms are unknown. We hypothesized that female protection may be conferred by enhanced production of cytochrome P450 (CYP)-dependent epoxyeicosatrienoic acids (EETs) that promote vasodilation as well as antiinflammatory and antiapoptotic pathways in the kidney. To test this hypothesis, we first analyzed the renal CYP-eicosanoid profile by liquid chromatography tandem mass spectrometry in male and female Lewis rats. Ischemia was induced through 45 min of left renal vessel clamping after right nephrectomy (n=6-8 per group). In non-ischemic controls, male and female kidneys stored almost identical amounts of EETs as well as 20-hydroxyeicosatetraenoic acid (20-HETE), both predominantly esterified into phospholipids, under basal non-ischemic conditions. 45 min of ischemia induced a massive release of EETs from membrane stores in females but not males. The free renal EET-levels reached 70.2±20.1 in females compared to only 4.6±1.3 ng/g in males. After ischemia, the ratio of free EETs to free 20-HETE was about 1:1 in females and 1:3 in males. Next, we proved the functional importance of EETs in renal protection by pretreating males with a synthetic EET-agonist (12-HUDE) and females with a selective EET-antagonist (14,15-EEZE-mSI). As analyzed two days after reperfusion, the EET-agonist protected males against loss of creatinine clearance (1.03±0.18 vs. 0.26±0.02 ml/min, p<0.01 vs. vehicle, compared to 1.28±0.06 ml/min in sham control). Females were rendered susceptible to I/R-injury by the EET-antagonist (creatinine clearance: 0.25±0.05 vs. 0.67±0.04; p<0.01 vs. vehicle, compared to 0.81±0.04 ml/min in sham control). Changes in inflammatory cell infiltration and tubular apoptosis paralleled these effects on renal function. Our results indicate that female rats are protected against renal I/R-injury by enhanced ischemia-induced EET-release and demonstrate that renal protection can be transferred to males using synthetic EET-agonists.

Abstract 12873: Blood Transfusion and the Risk of Contrast-Induced Nephropathy Among Acute Coronary Syndrome Patients Undergoing Percutaneous Coronary Intervention

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Wassef Karrowni ◽  
Amit N Vora ◽  
Dadi Dai ◽  
Daniel Wojdyla ◽  
Habib Dakik ◽  
...  
Keyword(s):  
Acute Coronary Syndrome ◽  
Blood Transfusion ◽  
Primary Outcome ◽  
Kidney Injury ◽  
Coronary Intervention ◽  
Contrast Induced Nephropathy ◽  
Coronary Syndrome ◽  
Post Procedure ◽  
Lower Baseline ◽  
Percutaneous Coronary

Introduction: Emerging scientific and clinical evidence suggests that blood transfusion might be risk factor for acute kidney injury. Hypothesis: Blood transfusion is independently associated with contrast-induced nephropathy (CIN) in acute coronary syndrome (ACS) patients undergoing PCI. Methods: Retrospective cohort study from the NCDR CathPCI Registry (2009-2014) (n=1,756,864). Primary outcome was CIN defined as rise in serum creatinine peak post-procedure ≥ 0.5 mg/dl or ≥ 25% above baseline. Results: CIN developed in 9.0% of the cohort; these patients were older (66.0 vs. 64.0 years; P<0.01), more often female (43.2% vs. 31.9%; P<0.01), and had more baseline comorbidities including DM (46.1%), hypertension (85.1%), and lower baseline GFR. Blood transfusion was utilized in 38,626 (2.2%) of patients. The adjusted OR for the risk of CIN with transfusion in the overall sample, patients with major bleeding, and patients with no bleeding were 4.87 (4.71-5.04), 2.21 (2.12-2.31), and 4.80 (4.40 - 5.24) respectively (Table). Association of CIN with transfusion was significantly increased across all pre-procedure hemoglobin (Hgb) levels and in stepwise fashion with increasing Hgb levels and regardless of post-procedure bleeding (Hgb &lt=10: adjusted OR (95%CI) 2.90 (2.75-3.05); Hgb &gt10 to &lt=13: 5.26 (5.06-5.48); Hgb &gt13 to &lt=15: 6.37 (5.99-6.78); Hgb &gt15 g/dl: 7.03 (6.43-7.67); Ptrend <0.01). Conclusions: Blood transfusion is strongly associated with CIN in ACS patients undergoing PCI. Whether a restrictive blood transfusion strategy lowers the risk of contrast nephropathy should be investigated.

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.

Molecular Mechanisms of Renal Ischemic Conditioning Strategies

2015 ◽  
Vol 55 (3) ◽  
pp. 151-183 ◽  
Author(s):  
Casper Kierulf-Lassen ◽  
Gertrude J. Nieuwenhuijs-Moeke ◽  
Nicoline V. Krogstrup ◽  
Mihai Oltean ◽  
Bente Jespersen ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Molecular Mechanisms ◽  
Defense Mechanism ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Clinical Settings ◽  
Ischemic Conditioning ◽  
Protective Signaling ◽  
Survival Mechanisms

Ischemia-reperfusion injury is the leading cause of acute kidney injury in a variety of clinical settings such as renal transplantation and hypovolemic and/or septic shock. Strategies to reduce ischemia-reperfusion injury are obviously clinically relevant. Ischemic conditioning is an inherent part of the renal defense mechanism against ischemia and can be triggered by short periods of intermittent ischemia and reperfusion. Understanding the signaling transduction pathways of renal ischemic conditioning can promote further clinical translation and pharmacological advancements in this era. This review summarizes research on the molecular mechanisms underlying both local and remote ischemic pre-, per- and postconditioning of the kidney. The different types of conditioning strategies in the kidney recruit similar powerful pro-survival mechanisms. Likewise, renal ischemic conditioning mobilizes many of the same protective signaling pathways as in other organs, but differences are recognized.

scholarly journals Epoxide metabolites of arachidonate and docosahexaenoate function conversely in acute kidney injury involved in GSK3β signaling

2017 ◽  
Vol 114 (47) ◽  
pp. 12608-12613 ◽  
Author(s):  
Bing-Qing Deng ◽  
Ying Luo ◽  
Xin Kang ◽  
Chang-Bin Li ◽  
Christophe Morisseau ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Therapeutic Strategies ◽  
Epoxyeicosatrienoic Acid ◽  
Renal Tubular

Acute kidney injury (AKI) causes severe morbidity and mortality for which new therapeutic strategies are needed. Docosahexaenoic acid (DHA), arachidonic acid (ARA), and their metabolites have various effects in kidney injury, but their molecular mechanisms are largely unknown. Here, we report that 14 (15)-epoxyeicosatrienoic acid [14 (15)-EET] and 19 (20)-epoxydocosapentaenoic acid [19 (20)-EDP], the major epoxide metabolites of ARA and DHA, respectively, have contradictory effects on kidney injury in a murine model of ischemia/reperfusion (I/R)-caused AKI. Specifically, 14 (15)-EET mitigated while 19 (20)-EDP exacerbated I/R kidney injury. Manipulation of the endogenous 19 (20)-EDP or 14 (15)-EET by alteration of their degradation or biosynthesis with selective inhibitors resulted in anticipated effects. These observations are supported by renal histological analysis, plasma levels of creatinine and urea nitrogen, and renal NGAL. The 14 (15)-EET significantly reversed the I/R-caused reduction in glycogen synthase kinase 3β (GSK3β) phosphorylation in murine kidney, dose-dependently inhibited the hypoxia/reoxygenation (H/R)-caused apoptosis of murine renal tubular epithelial cells (mRTECs), and reversed the H/R-caused reduction in GSK3β phosphorylation in mRTECs. In contrast, 19 (20)-EDP dose-dependently promoted H/R-caused apoptosis and worsened the reduction in GSK3β phosphorylation in mRTECs. In addition, 19 (20)-EDP was more metabolically stable than 14 (15)-EET in vivo and in vitro. Overall, these epoxide metabolites of ARA and DHA function conversely in I/R-AKI, possibly through their largely different metabolic stability and their opposite effects in modulation of H/R-caused RTEC apoptosis and GSK3β phosphorylation. This study provides AKI patients with promising therapeutic strategies and clinical cautions.

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