scholarly journals Chemokine Receptor CX3CR1 Regulates Renal Interstitial Fibrosis after Ischemia-Reperfusion Injury

2006 ◽  
Vol 169 (2) ◽  
pp. 372-387 ◽  
Author(s):  
Kengo Furuichi ◽  
Ji-Liang Gao ◽  
Philip M. Murphy
Keyword(s):  
Reperfusion Injury ◽  
Chemokine Receptor ◽  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Renal Interstitial Fibrosis ◽  
Receptor Cx3cr1

Abstract 428: Pharmacologic and Activated Fibroblast-specific Gβγ-GRK2 Inhibition is Protective Following Ischemia Reperfusion Injury

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Joshua G Travers ◽  
Fadia A Kamal ◽  
Michelle L Nieman ◽  
Michelle A Sargent ◽  
Jeffery D Molkentin ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Reperfusion Injury ◽  
G Protein ◽  
Knockout Mice ◽  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Ventricular Compliance

Heart failure is a devastating disease characterized by chamber remodeling, interstitial fibrosis and reduced ventricular compliance. Cardiac fibroblasts are responsible for extracellular matrix homeostasis, however upon injury or pathologic stimulation, these cells transform to a myofibroblast phenotype and play a fundamental role in myocardial fibrosis and remodeling. Chronic sympathetic overstimulation induces excess signaling through G protein βγ subunits and ultimately the pathologic activation of G protein-coupled receptor kinase 2 (GRK2). We hypothesized that Gβγ-GRK2 inhibition plays an important role in the cardiac fibroblast to attenuate pathologic myofibroblast activation and cardiac remodeling. To investigate this hypothesis, mice were subjected to ischemia/reperfusion (I/R) injury and treated with the small molecule Gβγ-GRK2 inhibitor gallein. While animals receiving vehicle demonstrated a reduction in overall cardiac function as measured by echocardiography, mice treated with gallein exhibited nearly complete preservation of cardiac function and reduced fibrotic scar formation. We next sought to establish the cell specificity of this compound by treating inducible cardiomyocyte- and activated fibroblast-specific GRK2 knockout mice post-I/R. Although we observed modest restoration in cardiac function in cardiomyocyte-specific GRK2 null mice, treatment of these mice with gallein resulted in further protection against myocardial dysfunction following injury, suggesting a functional role in other cardiac cell types, including fibroblasts. Activated fibroblast-specific GRK2 knockout mice were also subjected to ischemia/reperfusion injury; these animals displayed preserved myocardial function and reduced collagen deposition compared to littermate controls following injury. Furthermore, systemic Gβγ-GRK2 inhibition by gallein did not appear to confer further protection over activated fibroblast-specific GRK2 ablation alone. In summary, these findings suggest a potential therapeutic role for Gβγ-GRK2 inhibition in limiting pathologic myofibroblast activation, interstitial fibrosis and heart failure progression.

scholarly journals miR-21 in ischemia/reperfusion injury: a double-edged sword?

2014 ◽  
Vol 46 (21) ◽  
pp. 789-797 ◽  
Author(s):  
Xialian Xu ◽  
Alison J. Kriegel ◽  
Xiaoyan Jiao ◽  
Hong Liu ◽  
Xiaowen Bai ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Hypoxia Inducible Factor ◽  
Renal Interstitial Fibrosis ◽  
Rna Molecules ◽  
Programmed Cell Death 4 ◽  
Proapoptotic Gene

MicroRNAs (miRNAs or miRs) are endogenous, small RNA molecules that suppress expression of targeted mRNA. miR-21, one of the most extensively studied miRNAs, is importantly involved in divergent pathophysiological processes relating to ischemia/reperfusion (I/R) injury, such as inflammation and angiogenesis. The role of miR-21 in renal I/R is complex, with both protective and pathological pathways being regulated by miR-21. Preconditioning-induced upregulation of miR-21 contributes to the protection against subsequent renal I/R injury through the targeting of genes such as the proapoptotic gene programmed cell death 4 and interactions between miR-21 and hypoxia-inducible factor. Conversely, long-term elevation of miR-21 may be detrimental to the organ by promoting the development of renal interstitial fibrosis following I/R injury. miR-21 is importantly involved in several pathophysiological processes related to I/R injury including inflammation and angiogenesis as well as the biology of stem cells that could be used to treat I/R injury; however, the effect of miR-21 on these processes in renal I/R injury remains to be studied.

scholarly journals Cu/Zn-Superoxide Dismutase Gene Attenuates Ischemia-Reperfusion Injury in the Rat Kidney

2001 ◽  
Vol 12 (12) ◽  
pp. 2691-2700 ◽  
Author(s):  
Ming Yin ◽  
Michael D. Wheeler ◽  
Henry D. Connor ◽  
Zhi Zhong ◽  
Hartwig Bunzendahl ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Recombinant Adenovirus ◽  
Interstitial Fibrosis ◽  
Rat Kidney ◽  
Ischemia Reperfusion ◽  
Interleukin 1 ◽  
Tubular Atrophy ◽  
Necrosis Factor Alpha

ABSTRACT. Evidence has accumulated for a role of toxic oxygen radicals in the pathogenesis of ischemia-reperfusion injury in the kidney. The aim of this study was to evaluate the hypothesis that reducing postischemic renal injury is possible by delivery of the gene for the antioxidant enzyme superoxide dismutase (SOD). Female Sprague-Dawley rats received intravenous injections of recombinant adenovirus (1 × 109 pfu) containing the transgenes for Escherichia coli β-galactosidase (Ad-LacZ, as control) or human Cu/Zn-SOD (Ad-SOD). Three days later, renal ischemia was produced by cross-clamping the left renal vessels for 60 min. The right kidney was removed before reperfusion and processed for the transgene. Renal SOD protein and activity in rats given Ad-SOD was 2.5-fold higher than from the animals receiving Ad-LacZ. Urinary lactate dehydrogenase concentrations were elevated by ischemia-reperfusion in the Ad-LacZ group (1403 ± 112 U/L), yet values were 50% lower in Ad-SOD-treated rats. Free radical production was elevated by ischemia-reperfusion but was significantly lower in SOD-treated animals. Importantly, on postischemic day 1, glomerular filtration rates were reduced to 0.21 ml/min per 100 g in the Ad-LacZ group, whereas values remained significantly higher (0.39) in the Ad-SOD group. Two weeks after ischemia-reperfusion, inflammation, interstitial fibrosis, tubular atrophy and tissue levels of tumor necrosis factor alpha and interleukin-1 were significantly higher in the Ad-LacZ-treated than in Ad-SOD-treated rats. In conclusion, these results indicate that SOD expression can be increased by delivery of the sod gene to the kidney by intravenous injection and that sod gene transduction minimized ischemia-reperfusion-induced acute renal failure.

scholarly journals p38-Regulated/activated protein kinase plays a pivotal role in protecting heart against ischemia-reperfusion injury and preserving cardiac performance

2019 ◽  
Vol 317 (3) ◽  
pp. C525-C533 ◽  
Author(s):  
Yu Tina Zhao ◽  
Jianfeng Du ◽  
Naohiro Yano ◽  
Hao Wang ◽  
Jianguo Wang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Cardiac Performance ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

p38-Regulated/activated protein kinase (PRAK) plays a critical role in modulating cellular survival and biological function. However, the function of PRAK in the regulation of myocardial ischemic injury remains unknown. This study is aimed at determining the function of PRAK in modulating myocardial ischemia-reperfusion injury and myocardial remodeling following myocardial infarction. Hearts were isolated from adult male homozygous PRAK−/− and wild-type mice and subjected to global ischemia-reperfusion injury in Langendorff isolated heart perfusion. PRAK−/− mice mitigated postischemic ventricular functional recovery and decreased coronary effluent. Moreover, the infarct size in the perfused heart was significantly increased by deletion of PRAK. Western blot showed that deletion of PRAK decreased the phosphorylation of ERK1/2. Furthermore, the effect of deletion of PRAK on myocardial function and remodeling was also examined on infarcted mice in which the left anterior descending artery was ligated. Echocardiography indicated that PRAK−/− mice had accelerated left ventricular systolic dysfunction, which was associated with increased hypertrophy in the infarcted area. Deletion of PRAK augmented interstitial fibrosis and terminal deoxynucleotidyl transferase nick-end labeling (TUNEL)-positive myocytes. Furthermore, immunostaining analysis shows that CD31-postive vascular density and α-smooth muscle actin capillary staining decreased significantly in PRAK−/− mice. These results indicate that deletion of PRAK enhances susceptibility to myocardial ischemia-reperfusion injury, attenuates cardiac performance and angiogenesis, and increases interstitial fibrosis and apoptosis in the infarcted hearts.

scholarly journals CXC chemokine receptor-1 is expressed by hepatocytes and regulates liver recovery after hepatic ischemia/reperfusion injury

Hepatology ◽  
2010 ◽  
Vol 53 (1) ◽  
pp. 261-271 ◽  
Author(s):  
Callisia Clarke ◽  
Satoshi Kuboki ◽  
Nozomu Sakai ◽  
Kevin R. Kasten ◽  
Amit D. Tevar ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Chemokine Receptor ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Hepatic Ischemia ◽  
Cxc Chemokine ◽  
Hepatic Ischemia Reperfusion ◽  
Chemokine Receptor 1

scholarly journals Tubular GM-CSF Promotes Late MCP-1/CCR2-Mediated Fibrosis and Inflammation after Ischemia/Reperfusion Injury

2019 ◽  
Vol 30 (10) ◽  
pp. 1825-1840 ◽  
Author(s):  
Leyuan Xu ◽  
Diana Sharkey ◽  
Lloyd G. Cantley
Keyword(s):  
Reperfusion Injury ◽  
Immune Cells ◽  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Tubular Injury ◽  
Wild Type ◽  
Tubular Cells ◽  
Gm Csf ◽  
Renal Tubular Cells

BackgroundAfter bilateral kidney ischemia/reperfusion injury (IRI), monocytes infiltrate the kidney and differentiate into proinflammatory macrophages in response to the initial kidney damage, and then transition to a form that promotes kidney repair. In the setting of unilateral IRI (U-IRI), however, we have previously shown that macrophages persist beyond the time of repair and may promote fibrosis.MethodsMacrophage homing/survival signals were determined at 14 days after injury in mice subjected to U-IRI and in vitro using coculture of macrophages and tubular cells. Mice genetically engineered to lack Ccr2 and wild-type mice were treated ±CCR2 antagonist RS102895 and subjected to U-IRI to quantify macrophage accumulation, kidney fibrosis, and inflammation 14 and 30 days after the injury.ResultsFailure to resolve tubular injury after U-IRI results in sustained expression of granulocyte-macrophage colony-stimulating factor by renal tubular cells, which directly stimulates expression of monocyte chemoattractant protein-1 (Mcp-1) by macrophages. Analysis of CD45+ immune cells isolated from wild-type kidneys 14 days after U-IRI reveals high-level expression of the MCP-1 receptor Ccr2. In mice lacking Ccr2 and wild-type mice treated with RS102895, the numbers of macrophages, dendritic cells, and T cell decreased following U-IRI, as did the expression of profibrotic growth factors and proimflammatory cytokines. This results in a reduction in extracellular matrix and kidney injury markers.ConclusionsGM-CSF–induced MCP-1/CCR2 signaling plays an important role in the cross-talk between injured tubular cells and infiltrating immune cells and myofibroblasts, and promotes sustained inflammation and tubular injury with progressive interstitial fibrosis in the late stages of U-IRI.

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