scholarly journals Fetuin-A is a HIF target that safeguards tissue integrity during hypoxic stress

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Stefan Rudloff ◽  
Mathilde Janot ◽  
Stephane Rodriguez ◽  
Kevin Dessalle ◽  
Willi Jahnen-Dechent ◽  
...  
Keyword(s):  
Protective Factor ◽  
Soft Tissues ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Macrophage Polarization ◽  
Kidney Size ◽  
Fetuin A ◽  
Increased Risk ◽  
Mineral Stress ◽  
Adult Model

AbstractIntrauterine growth restriction (IUGR) is associated with reduced kidney size at birth, accelerated renal function decline, and increased risk for chronic kidney and cardiovascular diseases in adults. Precise mechanisms underlying fetal programming of adult diseases remain largely elusive and warrant extensive investigation. Setting up a mouse model of hypoxia-induced IUGR, fetal adaptations at mRNA, protein and cellular levels, and their long-term functional consequences are characterized, using the kidney as a readout. Here, we identify fetuin-A as an evolutionary conserved HIF target gene, and further investigate its role using fetuin-A KO animals and an adult model of ischemia-reperfusion injury. Beyond its role as systemic calcification inhibitor, fetuin-A emerges as a multifaceted protective factor that locally counteracts calcification, modulates macrophage polarization, and attenuates inflammation and fibrosis, thus preserving kidney function. Our study paves the way to therapeutic approaches mitigating mineral stress-induced inflammation and damage, principally applicable to all soft tissues.

In vivo and In vitro PPAR-y Activation Decreases M1-Macrophage Polarization and Improves Liver Ischemia Reperfusion Injury

2018 ◽  
Vol 102 ◽  
pp. S708
Author(s):  
Ivan Linares ◽  
Agata Bartczak ◽  
Kaveh Farrokhi ◽  
Dagmar Kollmann ◽  
Moritz Kaths ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Macrophage Polarization ◽  
Liver Ischemia ◽  
M1 Macrophage

Abstract MP58: Tissue And Sex Specific Effects Of Gstm1 Deletion In Mouse Models

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Yves Wang ◽  
Nhu Nguyen ◽  
Keith Nehrke ◽  
Paul S Brookes ◽  
Thu H Le
Keyword(s):  
Oxidative Stress ◽  
Antioxidant Enzymes ◽  
Mouse Model ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Antioxidant Properties ◽  
Iri Model ◽  
Increased Risk ◽  
Study Gene Expression

The glutathione S-transferase ( Gst ) gene family encodes antioxidant enzymes. In humans, a common null allele deletion variant of GST μ-1 ( GSTM1 ) is highly prevalent across populations and is associated with increased risk and progression of various diseases. Using a Gstm1 knockout (KO) mouse model, we previously showed that KO mice with angiotensin II-induced hypertension (HTN) have increased kidney injury compared to wild-type (WT) controls, mediated by elevated oxidative stress. In the same mouse model, we have recently reported that in a Langendorff-perfused cardiac ischemia-reperfusion injury (IRI) model, where damage is also mediated by oxidative stress, male KO hearts are protected while females are not. Here, we investigated the molecular mechanisms for this difference in male hearts. WT and KO mice of both sexes were studied at 12-20 weeks of age. Hearts were snap frozen at baseline and after 25 min of global ischemia, and kidneys were collected at baseline and 4 weeks following HTN induction. A panel of 18 Gst genes were probed by qPCR from baseline hearts and kidneys of both sexes. Global metabolites were assayed using Metabolon, Inc. from hearts of both sexes and kidneys of males, at both baseline and diseased states. Analysis by qPCR (n = 3/group) showed that male, but not female, KO hearts had upregulation of other Gst s. In contrast, no significant differences between were found in male kidneys. Metabolomics (n = 6/group) detected 695 metabolites in hearts and 926 in kidneys. There were increases in several metabolites in KO vs. WT hearts including those with antioxidant properties. Notably, increases in carnosine and anserine were observed in KO male hearts but not in female hearts, while that of other antioxidant-related metabolites were observed in hearts of both sexes, but not in kidneys. HTN induced significant increases in metabolites in KO vs. WT kidneys in the pathways related to and linking methionine, cysteine, and glutathione, which were not observed in hearts. In this study, gene expression and metabolites suggest that the mechanisms compensating for the loss of GSTM1 are both tissue and sex specific. The resulting differences in antioxidant enzymes and metabolites may explain the unexpected protection for male Gstm1 KO hearts in IRI.

Abstract 16991: Cardiosphere-derived Cell Exosomes Confer Acute Cardioprotection Following Ischemia-reperfusion Injury Through Macrophage Polarization (Best of Basic Science Abstract)

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Geoffrey de Couto ◽  
Nupur Makkar ◽  
Eduardo Marbán
Keyword(s):  
Noncoding Rna ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Macrophage Polarization ◽  
Dose Finding ◽  
Random Allocation ◽  
Dependent Manner ◽  
Phagocytic Capacity ◽  
Cardioprotective Effects ◽  
Wistar Kyoto

Introduction: Cardiosphere-Derived Cells (CDCs) exert both regenerative and cardioprotective effects following ischemic insult to the myocardium. The regenerative effects are mimicked by human CDC exosomes (CDC exo ), secreted nanovesicular entities that contain CDC-specific payloads of protein and noncoding RNA. Here we demonstrate that, CDC exo reduce infarct size and macrophage (Mf) infiltration when infused via the intracoronary route following ischemia/reperfusion (I/R) injury. Methods & Results: To examine the safety and efficacy of CDC exo , we performed a dose-finding study in Wistar-Kyoto rats (aged 8-12 weeks). Exosomes were precipitated from conditioned media collected from human CDCs or Fibroblasts [Fb, as a control] grown in serum-free media for 15 days. Exosome protein quantity, surface marker expression, and particle number were assessed prior to delivery. For in vivo analyses, rats underwent 45 minutes of ischemia followed by 20 minutes of reperfusion, then intracoronary infusion by random allocation of either Fb exosomes (Fb exo ) or CDC exo . Two days later, histological analysis revealed that CDC exo reduced infarct mass (CDC exo : 6.38% vs. Fb exo : 13.32%; p<0.05) and CD68 + Mf infiltration (CDC exo : 183.5/FOV vs. Fb exo : 302.1/FOV; p<0.05). In vitro, Mf uptake of exosomes and polarization based on gene expression profile ( Arg1, Vegfa, Il4ra ) occurred in a time-dependent manner. The phagocytic capacity of CDC exo -primed Mf was elevated relative to Fb exo -, M1-, or M2-polarized Mf (CDC exo : 76.8%; Fb exo : 38.3%; M1: 52.2%; M2: 33.9%; p<0.05). Conclusions: CDC exo are cardioprotective when delivered via the intracoronary route 20 min post-I/R. These data demonstrate that exosomes secreted by CDCs (but not by fibroblasts) recapitulate the cardioprotective effects of CDCs (cellular postconditioning; Kanazawa et al, Circ HF 2015; de Couto et al, JCI 2015). Like CDCs, CDC exo modulate the Mf infiltrate in the heart post-I/R and distinctively polarize Mf. The data support the conjecture that CDC exo mediate the cardioprotective effects of CDCs via effects on Mf.

Effect of Ischemia and Reperfusion on Skeletal Muscle Damage

2010 ◽  
Author(s):  
Sandra Loerakker ◽  
Emmy Manders ◽  
Gustav J. Strijkers ◽  
Frank P. T. Baaijens ◽  
Dan L. Bader ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Damage ◽  
Soft Tissues ◽  
Ischemia Reperfusion Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Ischemia And Reperfusion ◽  
Skin Damage ◽  
Deep Tissue ◽  
Skeletal Muscle Damage

Sustained mechanical loading of soft tissues covering bony prominences, as experienced by bedridden and wheelchair-bound individuals, may cause skeletal muscle damage. This can result in a condition termed pressure-related deep tissue injury (DTI), a severe kind of pressure ulcer that initiates in deep tissue layers, and progresses towards the skin. Damage pathways leading to DTI can involve ischemia, ischemia/reperfusion injury, impaired lymphatic drainage, and sustained tissue deformation. Recently, we have provided evidence that in a controlled animal model, deformation is the main trigger for damage within a 2h loading period [1,2]. However, ischemia and reperfusion may play a more important role in the damage process during prolonged loading periods.

scholarly journals Netrin-1-treated macrophages protect the kidney against ischemia-reperfusion injury and suppress inflammation by inducing M2 polarization

2013 ◽  
Vol 304 (7) ◽  
pp. F948-F957 ◽  
Author(s):  
Punithavathi Vilapakkam Ranganathan ◽  
Calpurnia Jayakumar ◽  
Ganesan Ramesh
Keyword(s):  
Reperfusion Injury ◽  
Macrophage Activation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Macrophage Polarization ◽  
Kidney Injury ◽  
In Vitro Studies ◽  
Arginase 1 ◽  
M2 Polarization

Improper macrophage activation is pathogenically linked to various metabolic, inflammatory, and immune disorders. Therefore, regulatory proteins controlling macrophage activation have emerged as important new therapeutic targets. We recently demonstrated that netrin-1 regulates inflammation and infiltration of monocytes and ameliorates ischemia-reperfusion-induced kidney injury. However, it was not known whether netrin-1 regulates the phenotype of macrophages and the signaling mechanism through which it might do this. In this study, we report novel mechanisms underlying netrin-1's effects on macrophages using in vivo and in vitro studies. Overexpression of netrin-1 in spleen and kidney of transgenic mice increased expression of arginase-1, IL-4, and IL-13 and decreased expression of COX-2, indicating a phenotypic switch in macrophage polarization toward an M2-like phenotype. Moreover, flow cytometry analysis showed a significant increase in mannose receptor-positive macrophages in spleen compared with wild type. In vitro, netrin-1 induced the expression of M2 marker expression in bone marrow-derived macrophages, peritoneal macrophages, and RAW264.7 cells, and suppressed IFNγ-induced M1 polarization and production of inflammatory mediators. Adoptive transfer of netrin-1-treated macrophages suppressed inflammation and kidney injury against ischemia-reperfusion. Netrin-1 activated PPAR pathways and inhibition of PPAR activation abolished netrin-1-induced M2 polarization and suppression of cytokine production. Consistent with in vitro studies, administration of PPAR antagonist to mice abolished the netrin-1 protective effects against ischemia-reperfusion injury of the kidney. These findings illustrate that netrin-1 regulates macrophage polarization through PPAR pathways and confers anti-inflammatory actions in inflammed kidney tissue.

scholarly journals SS-31 Protects Liver from Ischemia-Reperfusion Injury via Modulating Macrophage Polarization

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Longcheng Shang ◽  
Haozhen Ren ◽  
Shuai Wang ◽  
Hanyi Liu ◽  
Anyin Hu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Injury ◽  
Reperfusion Injury ◽  
Liver Damage ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Macrophage Polarization ◽  
Protective Effects ◽  
Inflammation Response ◽  
Stat3 Signaling

Ischemia-reperfusion injury (IRI) is a common complication in liver surgeries. It is a focus to discover effective treatments to reduce ischemia-reperfusion injury. Previous studies show that oxidative stress and inflammation response contribute to the liver damage during IRI. SS-31 is an innovated mitochondrial-targeted antioxidant peptide shown to scavenge reactive oxygen species and decrease oxidative stress, but the protective effects of SS-31 against hepatic IRI are not well understood. The aim of our study is to investigate whether SS-31 could protect the liver from damages induced by IRI and understand the protective mechanism. The results showed that SS-31 treatment can significantly attenuate liver injury during IRI, proved by HE staining, serum ALT/AST, and TUNEL staining which can assess the degree of liver damage. Meanwhile, we find that oxidative stress and inflammation were significantly suppressed after SS-31 administration. Furthermore, the mechanism revealed that SS-31 can directly decrease ROS production and regulate STAT1/STAT3 signaling in macrophages, thus inhibiting macrophage M1 polarization. The proinflammation cytokines are then significantly reduced, which suppress inflammation response in the liver. Taken together, our study discovered that SS-31 can regulate macrophage polarization through ROS scavenging and STAT1/STAT3 signaling to ameliorate liver injury; the protective effects against hepatic IRI suggest that SS-31 may be an appropriate treatment for liver IRI in the clinic.

scholarly journals Using Verapamil as Protective Factor in Renal Ischemia Reperfusion Injury During Anatrophic Nephrolithotomy

2007 ◽  
Vol 7 (3) ◽  
pp. 235-238 ◽  
Author(s):  
Damir Aganović ◽  
Benjamin Kulovac ◽  
Alden Prcić ◽  
Osman Hadžiosmanović
Keyword(s):  
Reperfusion Injury ◽  
Kidney Failure ◽  
Protective Factor ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Preoperative Evaluation ◽  
Postoperative Outcome ◽  
Chronic Kidney Failure ◽  
Intravenous Urography ◽  
Channel Blockers

Anatrophic nephrolithotomy (ANL) in the selected cases represents the method of choice in the treatment of staghorn calculi. We evaluated postoperative outcome of patients subjected to standard ANL that received 10 mg of Verapamil immediately before declamping renal artery, due to prevention of reperfusion injury. From 2002 to 2005, 18 nephrolithotomies were performed on 15 patients, in the Urology Clinic, University of Sarajevo Clinics Centre. Preoperative evaluation included intravenous urography and radionuclide renal scans which had been repeated 6 months after the operations. 10 males and 5 females were operated with mean age of 45 years. Urography and renal scans showed severe calyceal distortion and infundibular stenosis in 83% cases, complicated with ureteropelvic junction obstruction in 55% cases. Chronic kidney failure was present in 60% patients. Mean operative time was 150 minutes, with mean cold ischemia time of 61 minutes and mean blood loss of 300ml. There were five minor postoperative complications. Residual small calculi were found in 3 patients. Kidney function was stabilized in the patients suffering from chronic kidney failure, which was proved by radio nuclide imaging. ANL improved by using calcium channel blockers as a protective factor for reperfusion injury proved to be a good treatment choice with a low level of complications and noticeable stabilization and improvement of kidneys function.

scholarly journals Riclinoctaose Attenuates Renal Ischemia-Reperfusion Injury by the Regulation of Macrophage Polarization

2021 ◽  
Vol 12 ◽  
Author(s):  
Yang Zhao ◽  
Zhao Ding ◽  
Wenhao Ge ◽  
Junhao Liu ◽  
Xi Xu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Macrophage Polarization ◽  
Renal Ischemia ◽  
M2 Macrophage ◽  
Mouse Bone Marrow ◽  
M1 Macrophage ◽  
Renal Ischemia Reperfusion Injury

Renal ischemia-reperfusion injury is a major trigger of acute kidney injury and leads to permanent renal impairment, and effective therapies remain unresolved. Riclinoctaose is an immunomodulatory octasaccharide composed of glucose and galactose monomers. Here we investigated whether riclinoctaose protects against renal ischemia-reperfusion injury. In mice, pretreatment with riclinoctaose significantly improved renal function, structure, and the inflammatory response after renal ischemia-reperfusion. Flow cytometry analysis revealed that riclinoctaose inhibited ischemia-reperfusion-induced M1 macrophage polarization and facilitated M2 macrophage recruitment into the kidneys. In isolated mouse bone marrow-derived macrophages, pretreatment with riclinoctaose promoted the macrophage polarization toward M2-like phenotype. The inhibitor of Nrf-2/HO-1 brusatol diminished the effects of riclinoctaose on macrophage polarization. In mice, intravenous injection with riclinoctaose-pretreated bone marrow-derived macrophages also protected against renal ischemia-reperfusion injury. Fluorescence-labeled riclinoctaose specifically bound to the membrane of macrophages. Interfering with mDC-SIGN blocked the riclinoctaose function on M2 polarization of macrophages, consequently impairing the renoprotective effect of riclinoctaose. Our results revealed that riclinoctaose is a potential therapeutic agent in preventing renal ischemia-reperfusion injury.

scholarly journals Extracellular vesicle–encapsulated IL-10 as novel nanotherapeutics against ischemic AKI

2020 ◽  
Vol 6 (33) ◽  
pp. eaaz0748
Author(s):  
Tao-Tao Tang ◽  
Bin Wang ◽  
Min Wu ◽  
Zuo-Lin Li ◽  
Ye Feng ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Macrophage Polarization ◽  
Mammalian Target Of Rapamycin ◽  
Kidney Injury ◽  
Interleukin 10 ◽  
Extracellular Vesicle ◽  
M2 Macrophage ◽  
Renal Tubular ◽  
The Stability

Recently, extracellular vesicles (EVs) have been attracting strong research interest for use as natural drug delivery systems. We report an approach to manufacturing interleukin-10 (IL-10)–loaded EVs (IL-10+ EVs) by engineering macrophages for treating ischemic acute kidney injury (AKI). Delivery of IL-10 via EVs enhanced not only the stability of IL-10, but also its targeting to the kidney due to the adhesive components on the EV surface. Treatment with IL-10+ EVs significantly ameliorated renal tubular injury and inflammation caused by ischemia/reperfusion injury, and potently prevented the transition to chronic kidney disease. Mechanistically, IL-10+ EVs targeted tubular epithelial cells, and suppressed mammalian target of rapamycin signaling, thereby promoting mitophagy to maintain mitochondrial fitness. Moreover, IL-10+ EVs efficiently drove M2 macrophage polarization by targeting macrophages in the tubulointerstitium. Our study demonstrates that EVs can serve as a promising delivery platform to manipulate IL-10 for the effective treatment of ischemic AKI.

Abstract 15884: Cardiosphere-Derived Cells Confer Acute Cardioprotection Following Ischemia-Reperfusion Injury in Rats: Role of Macrophage Polarization

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Geoffrey de Couto ◽  
Hideaki Kanazawa ◽  
Eleni Tseliou ◽  
Linda Marbán ◽  
Eduardo Marbán
Keyword(s):  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Macrophage Polarization ◽  
Oxidant Stress ◽  
Gene Profiles ◽  
Wistar Kyoto ◽  
Inflammatory Response To Injury

Introduction: Cardiosphere-derived cells (CDCs) confer both cardioprotection and regeneration in acute myocardial infarction (MI). However, only long-term (>3 wks) post-MI endpoints have been studied, making it impossible to investigate the cardioprotective effects in isolation. Macrophages (MF) concentrate within the heart following ischemic injury as part of the inflammatory response to injury. Here we test the hypothesis that CDCs are cardioprotective by modifying MF within the myocardium post-MI. Methods & Results: Wistar-Kyoto rats (aged 8-12 wks) underwent 45 min of ischemia followed by 20 min of reperfusion, then intracoronary (i.c.) infusion of either saline or CDCs (5x10 5 ). The use of a 48 hr endpoint enabled the selective study of cardioprotection. CDC-treated animals had preserved ejection fraction (59.2% vs. 47.4%; p<0.001) and reduced infarct size (TTC; 6.3% vs. 13.6%; p<0.01). The finding that CDC-treated hearts contained fewer CD68 + MF (p<0.05) suggested a mechanistic role for MF, a conjecture which we tested in detail. MF isolated from CDC-treated hearts secreted lower amounts of proinflammatory cytokines ( Nos2, Tnf, Il1b ; p<0.05). Systemic depletion of MF with clodronate liposomes attenuated the benefits of CDC therapy post-MI (p<0.05). In vitro , MF conditioned by transwell exposure to CDCs (M CDC ) exhibited distinct gene profiles relative to proinflammatory M 1 or “healing” M 2 polarization states (M CDC : Il10 ; M 1 : Nos2 ; M 2 : Arg1, Pparg ). Adoptive transfer of selective MF populations into the heart (i.c.; 20 min post-reflow) revealed that M CDC , but not M 1 or M 2 MF, could recapitulate the reduction in infarct size (M CDC : 4.5%; M 1 : 14.0%; M 2 : 10.8%; p<0.05). In vitro co-culture shows that M CDC selectively reduce cardiomyocyte apoptosis following oxidant stress (M CDC : 9.9%; M 1 : 39.4%; M 2 : 37.4%; p<0.001). Conclusions: CDCs are cardioprotective when administered 20 min after reflow; the timing distinguishes this form of cardioprotection from preconditioning or ischemic postconditioning. Various lines of evidence indicate that CDCs work by polarizing MF toward a cardioprotective phenotype. The findings motivate further translational development of the adjunctive use of CDCs post-MI to limit infarct size.

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