A1 adenosine receptor knockout mice exhibit increased renal injury following ischemia and reperfusion

2004 ◽  
Vol 286 (2) ◽  
pp. F298-F306 ◽  
Author(s):  
H. Thomas Lee ◽  
Hua Xu ◽  
Samih H. Nasr ◽  
Jurgen Schnermann ◽  
Charles W. Emala
Keyword(s):  
Renal Function ◽  
Knockout Mice ◽  
Adenosine Receptor ◽  
Renal Injury ◽  
Renal Ischemia ◽  
Myeloperoxidase Activity ◽  
Ischemia And Reperfusion ◽  
Wild Type Littermate ◽  
Renal Histology

Controversy exists regarding the effect of A1 adenosine receptor (AR) activation in the kidney during ischemia and reperfusion (I/R) injury. We sought to further characterize the role of A1 ARs in modulating renal function after I/R renal injury using both pharmacological and gene deletion approaches in mice. A1 AR knockout mice (A1KO) or their wild-type littermate controls (A1WT) were subjected to 30 min of renal ischemia. Some A1WT mice were subjected to 30 min of renal ischemia with or without pretreatment with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) or 2-chrolo-cyclopentyladenosine (CCPA), selective A1 AR antagonist and agonist, respectively. Plasma creatinine and renal histology were compared 24 h after renal injury. A1KO mice exhibited significantly higher creatinines and worsened renal histology compared with A1WT controls following renal I/R injury. A1WT mice pretreated with the A1 AR antagonist or agonist demonstrated significantly worsened or improved renal function, respectively, after I/R injury. In addition, A1WT mice pretreated with DPCPX or CCPA showed significantly increased or reduced markers of renal inflammation, respectively (renal myeloperoxidase activity, renal tubular neutrophil infiltration, ICAM-1, TNF-α, and IL-1β mRNA expression), while demonstrating no differences in indicators of apoptosis. In conclusion, we demonstrate that endogenous or exogenous preischemic activation of A1 ARs protects against renal I/R injury in vivo via mechanisms leading to decreased necrosis and inflammation.

A3 adenosine receptor knockout mice are protected against ischemia- and myoglobinuria-induced renal failure

2003 ◽  
Vol 284 (2) ◽  
pp. F267-F273 ◽  
Author(s):  
H. Thomas Lee ◽  
Ayuko Ota-Setlik ◽  
Hua Xu ◽  
Vivette D. D'Agati ◽  
Marlene A. Jacobson ◽  
...  
Keyword(s):  
Renal Failure ◽  
Renal Function ◽  
Knockout Mice ◽  
Adenosine Receptor ◽  
Renal Injury ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Renal Protection ◽  
A3 Adenosine Receptor ◽  
Renal Histology

A3 adenosine receptor (AR) activation and inhibition worsen and improve, respectively, renal function after ischemia-reperfusion (I/R) injury in rats. We sought to further characterize the role of A3 ARs in modulating renal function after either I/R or myoglobinuric renal injury. A3 knockout mice had significantly lower plasma creatinines compared with C57 controls 24 h after I/R or myoglobinuric renal injury. C57 control mice pretreated with the A3 AR antagonist [3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5 dicarboxylate] or agonist [0.125 mg/kg N 6-(3-iodobenzyl)- N-methyl-5′-carbamoyladenosine (IB-MECA)] demonstrated improved or worsened renal function, respectively, after I/R or myoglobinuric renal injury. Higher doses of IB-MECA were lethal in C57 mice subjected to renal ischemia. H1 but not H2 histamine receptor antagonist prevented death in mice pretreated with IB-MECA before renal ischemia. Improvement in renal function was associated with significantly improved renal histology. In conclusion, preischemic A3 AR activation (0.125 mg/kg IB-MECA) exacerbated renal I/R injury in mice. Mice lacking A3 ARs or blocking A3 ARs in wild-type mice resulted in significant renal protection from ischemic or myoglobinuric renal failure.

Trehalose attenuates renal ischemia-reperfusion injury by enhancing autophagy and inhibiting oxidative stress and inflammation

2020 ◽  
Vol 318 (4) ◽  
pp. F994-F1005
Author(s):  
Suwen Liu ◽  
Yunwen Yang ◽  
Huiping Gao ◽  
Ning Zhou ◽  
Peipei Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Renal Function ◽  
Renal Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Ischemia ◽  
Renal Histology ◽  
Hypoxia Reoxygenation

Renal ischemia-reperfusion (IR) injury is one of the most common acute kidney injuries, but there is still a lack of effective treatment in the clinical setting. Trehalose (Tre), a natural disaccharide, has been demonstrated to protect against oxidative stress, inflammation, and apoptosis. However, whether it could protect against IR-induced renal injury needs to be investigated. In an in vivo experiment, C57BL/6J mice were pretreated with or without Tre (2 g/kg) through a daily single intraperitoneal injection from 3 days before renal IR surgery. Renal function, apoptosis, oxidative stress, and inflammation were analyzed to evaluate kidney injury. In an in vitro experiment, mouse proximal tubular cells were treated with or without Tre under a hypoxia/reoxygenation condition. Western blot analysis, autophagy flux detection, and apoptosis assay were performed to evaluate the level of autophagy and antiapoptotic effect of Tre. The in vivo results showed that the renal damage induced by IR was ameliorated by Tre treatment, as renal histology and renal function were improved and the enhanced protein levels of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin were blocked. Moreover, autophagy was activated by Tre pretreatment along with inhibition of the IR injury-induced apoptosis, oxidative stress, and inflammation. The in vitro results showed that Tre treatment activated autophagy and protected against hypoxia/reoxygenation-induced tubular cell apoptosis and oxidative stress. Our results demonstrated that Tre protects against IR-induced renal injury, possibly by enhancing autophagy and blocking oxidative stress, inflammation, and apoptosis, suggesting its potential use for the clinical treatment of renal IR injury.

A1 adenosine receptor knockout mice exhibit increased mortality, renal dysfunction, and hepatic injury in murine septic peritonitis

2005 ◽  
Vol 289 (2) ◽  
pp. F369-F376 ◽  
Author(s):  
George Gallos ◽  
Thomas D. Ruyle ◽  
Charles W. Emala ◽  
H. Thomas Lee
Keyword(s):  
Organ Dysfunction ◽  
Knockout Mice ◽  
Adenosine Receptor ◽  
Ischemia Reperfusion ◽  
Cecal Ligation ◽  
Intercellular Adhesion Molecule ◽  
Myeloperoxidase Activity ◽  
Wild Type ◽  
Wild Type Littermate ◽  
Septic Peritonitis

Sepsis is a leading cause of multiorgan dysfunction and death in hospitalized patients. Dysregulated inflammatory processes and apoptosis contribute to the pathogenesis of sepsis-induced organ dysfunction and death. A1 adenosine receptor (A1AR) activation reduces inflammation and apoptosis after ischemia-reperfusion injury. Therefore, we questioned whether A1AR-mediated reduction of inflammation and apoptosis could improve mortality and organ dysfunction in a murine model of sepsis. A1AR knockout mice (A1 knockout) and their wild-type (A1 wild-type) littermate controls were subjected to cecal ligation and double puncture (CLP) with a 20-gauge needle. A1 knockout mice or A1 wild-type mice treated with 1,3-dipropyl-8-cyclopentylxanthine (a selective A1AR antagonist) had a significantly higher mortality rate compared with A1 wild-type mice following CLP. Mice lacking endogenous A1ARs demonstrated significant elevations in plasma creatinine, alanine aminotransferase, aspartate aminotransferase, keratinocyte-derived chemokine, and tumor necrosis factor-α 24 h after induction of sepsis compared with wild-type mice. The renal corticomedullary junction from A1 knockout mice also exhibited increased myeloperoxidase activity, intercellular adhesion molecule-1 protein, and mRNA encoding proinflammatory cytokines compared with renal samples from A1 wild-type littermate controls. No difference in renal tubular apoptosis was detected between A1 knockout and A1 wild-type mice. We conclude that endogenous A1AR activation confers a protective effect in mice from septic peritonitis primarily by attenuating the hyperacute inflammatory response in sepsis.

Renal circulatory occlusion and local cooling

1959 ◽  
Vol 14 (2) ◽  
pp. 227-232 ◽  
Author(s):  
S. Birkeland ◽  
A. Vogt ◽  
J. Krog ◽  
C. Semb
Keyword(s):  
Renal Function ◽  
Body Temperature ◽  
Renal Artery ◽  
Clinical Application ◽  
Renal Ischemia ◽  
Local Cooling ◽  
Experimental Procedure ◽  
Reversible Lesion ◽  
Initial Depression

A method was developed for local kidney cooling in vivo, evaluated in dogs and applied clinically. In dogs a reversible lesion was not obtained if renal ischemia lasted beyond 1 hour at 37℃. Application of local cooling (10±5℃) extended the tolerance time to 7 hours, with clamping of the entire renal pedicle, and to 12 hours with occlusion of the renal artery alone. Exposure of the same kidney to a second occlusion period (up to 9 hr.) resulted in a reversible lesion. Renal function studies (CU, CIn, CPAH and TmPAH) showed the same pattern (initial depression and course of recovery) as after renal ischemia at body temperature. Initial depression was roughly paralleling the duration of clamping. Preischemic function values were, in most instances, reached 3 months following the experimental procedure. Physiological aspects of ‘local cooling’ are discussed and the advantages over general hypothermia are pointed out. The technique used for clinical application is described. Submitted on April 25, 1958

In vivo spectroscopic monitoring of renal ischemia and reperfusion in a rat model

2006 ◽  
Author(s):  
Rajesh N. Raman ◽  
Christopher D. Pivetti ◽  
Dennis L. Matthews ◽  
Christoph Troppmann ◽  
Stavros G. Demos
Keyword(s):  
Rat Model ◽  
Renal Ischemia ◽  
Ischemia And Reperfusion ◽  
Spectroscopic Monitoring

scholarly journals Mitochondria-Targeted Antioxidant Mito-Tempo Protects Against Aldosterone-Induced Renal Injury In Vivo

2017 ◽  
Vol 44 (2) ◽  
pp. 741-750 ◽  
Author(s):  
Wei Ding ◽  
Tingyan Liu ◽  
Xiao Bi ◽  
Zhiling Zhang
Keyword(s):  
Electron Microscopy ◽  
Renal Function ◽  
Nlrp3 Inflammasome ◽  
Renal Injury ◽  
Periodic Acid ◽  
Inflammasome Activation ◽  
Periodic Acid Schiff ◽  
Nlrp3 Inflammasome Activation

Background/Aims: Growing evidence suggests mitochondrial dysfunction (MtD) and the Nlrp3 inflammasome play critical roles in chronic kidney disease (CKD) progression. We previously reported that Aldosterone (Aldo)-induced renal injury in vitro is directly caused by mitochondrial reactive oxygen species (mtROS)-mediated activation of the Nlrp3 inflammasome. Here we aimed to determine whether a mitochondria-targeted antioxidant (Mito-Tempo) could prevent Aldo-induced kidney damage in vivo. Methods: C57BL/6J mice were treated with Aldo and/or Mito-Tempo (or ethanol as a control) for 4 weeks. Renal injury was evaluated by Periodic Acid-Schiff reagent or Masson’s trichrome staining and electron microscopy. ROS were measured by DCFDA fluorescence and ELISA. MtD was determined by real-time PCR and electron microscopy. Activation of the Nlrp3 inflammasome and endoplasmic reticulum stress (ERS) was detected via western blot. Results: Compared with control mice, Aldo-infused mice showed impaired renal function, increased mtROS production and MtD, Nlrp3 inflammasome activation, and elevated ERS. We showed administration of Mito-Tempo significantly improved renal function and MtD, and reduced Nlrp3 inflammasome activation and ERS in vivo. Conclusion: Mitochondria-targeted antioxidants may attenuate Aldo-infused renal injury by inhibiting MtD, the Nlrp3 inflammasome, and ERS in vivo. Therefore, targeting mtROS might be an effective strategy for preventing CKD.

CXCR4 antagonism as a therapeutic approach to prevent acute kidney injury

2014 ◽  
Vol 307 (7) ◽  
pp. F783-F797 ◽  
Author(s):  
A. Zuk ◽  
M. Gershenovich ◽  
Y. Ivanova ◽  
R. T. MacFarland ◽  
S. P. Fricker ◽  
...  
Keyword(s):  
Renal Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Myeloperoxidase Activity ◽  
Long Term Effects ◽  
Cxcr4 Antagonist ◽  
Hematopoietic Stem ◽  
Before And After

We examined whether antagonism of the CXCR4 receptor ameliorates the loss of renal function following ischemia-reperfusion. CXCR4 is ubiquitously expressed on leukocytes, known mediators of renal injury, and on bone marrow hematopoietic stem cells (HSCs). Plerixafor (AMD3100, Mozobil) is a small-molecule CXCR4 antagonist that mobilizes HSCs into the peripheral blood and also modulates the immune response in in vivo rodent models of asthma and rheumatoid arthritis. Treatment with plerixafor before and after ischemic clamping ameliorated kidney injury in a rat model of bilateral renal ischemia-reperfusion. Serum creatinine and blood urea nitrogen were significantly reduced 24 h after reperfusion, as were tissue injury and cell death. Plerixafor prevented the renal increase in the proinflammatory chemokines CXCL1 and CXCL5 and the cytokine IL-6. Flow cytometry of kidney homogenates confirmed the presence of significantly fewer leukocytes with plerixafor treatment; additionally, myeloperoxidase activity was reduced. AMD3465, a monocyclam analog of plerixafor, was similarly renoprotective. Four weeks postreperfusion, long-term effects included diminished fibrosis, inflammation, and ongoing renal injury. The mechanism by which CXCR4 inhibition ameliorates AKI is due to modulation of leukocyte infiltration and expression of proinflammatory chemokines/cytokines, rather than a HSC-mediated effect. The data suggest that CXCR4 antagonism with plerixafor may be a potential option to prevent AKI.

scholarly journals Functional consequences of inhibiting exocytosis of Weibel-Palade bodies in acute renal ischemia

2012 ◽  
Vol 302 (6) ◽  
pp. F713-F721 ◽  
Author(s):  
Kaoru Yasuda ◽  
Radovan Vasko ◽  
Peter Hayek ◽  
Brian Ratliff ◽  
Hasan Bicer ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Renal Injury ◽  
Inhibitory Effect ◽  
Renal Ischemia ◽  
Hematopoietic Stem ◽  
Aortic Endothelial Cells ◽  
Point Tracking ◽  
Inflammatory Protein ◽  
Acute Renal Ischemia

Exocytosis of Weibel-Palade bodies (WPB) represents a distinct response of endothelial cells to stressors, and local release of WPB contents leads to systemic escalation of this response. We synthesized a glycine-(Nα-Et)lysine-proline-arginine (ITF 1697) peptide that has a potential to inhibit exocytosis of WPB and protect microcirculation. Here, we confirmed an inhibitory effect of ITF 1697 using intravital videoimaging and point-tracking of individual organelles. In an in vivo study, mice were implanted with Alzet osmotic pumps (10 μg ITF 1697·kg−1·min−1 at volume of 1 μl/h) and subjected to renal ischemia (IRI). IRI resulted in marked renal injury and elevation of serum creatinine in mice treated with a vehicle. In contrast, renal injury and elevation of creatinine were significantly ameliorated in mice subjected to IRI and receiving ITF 1697. ITF 1697 prevented a systemic response to IRI: a significant surge in the levels of eotaxin and IL-8 (KC; both components of WPB), IL-1α, IL-1β, and RANTES was all prevented or blunted by the administration of ITF 1697, whereas the levels of an anti-inflammatory, IL-10, and macrophage inflammatory protein-1α were upregulated in ITF 1697-treated animals. En face staining of aortic endothelial cells showed that WPB were depleted after 40–180 min post-IRI, and this was significantly blunted in aortic preparations obtained from mice treated with ITF 1697. WPB exocytosis contributed to IRI-associated mobilization of endothelial progenitor cells and hematopoietic stem cells, and ITF 1697 blunted their mobilization. Unexpectedly, 1 mo after IRI, mice treated with ITF 1697 showed a significantly more pronounced degree of scarring than nontreated animals. In conclusion, 1) application of ITF 1697 inhibits exocytosis of WPB and IRI; 2) the systemic inflammatory response of IRI is in part due to the exocytosis of WPB and its blockade blunts it; and 3) ITF 1697 improves short-term renal function after IRI, but not the long-term fibrotic complications.

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