P0522INHIBITING 15-PGDH PREVENTS ISCHEMIC RENAL INJURY BY A PGE2/EP4 SIGNALING PATHWAY MEDIATING VASODILATION, INCREASED RENAL BLOOD FLOW, AND INCREASED ADENOSINE/A2A RECEPTOR

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Byeong Woo KIm ◽  
Sun hee Kim ◽  
Ki beom Bae
Keyword(s):  
Blood Flow ◽  
Renal Blood Flow ◽  
Renal Injury ◽  
Ischemia Reperfusion ◽  
Adenosine A2a Receptor ◽  
Vehicle Group ◽  
Control Group ◽  
Protective Effects ◽  
A2a Receptor ◽  
Adenosine A2a

Abstract Background and Aims We demonstrate the marked activity of SW033291, an inhibitor of 15-hydoxyprostaglandin dehydrogenase (15-PGDH), in preventing acute kidney injury (AKI) in a murine model of ischemia reperfusion injury (IRI). AKI due to ischemic injury represents a significant clinical problem. Prostaglandin E2 (PGE2) is vasodilator in the kidney, but is rapidly degraded in vivo due to catabolism by 15-PGDH. We investigated the potential of SW033291, a potent and specific 15-PGDH inhibitor, as prophylactic treatment for ischemic AKI. Method 10-week aged male C57/BL6 mice were randomly allocated to five groups (n=8 to 15 in each group): the sham-control group, sham-SW033291 group, IRI-vehicle group, IRI-indomethacin group and the IRI-SW033291 group. IRI were induced by clamping bilateral renal artery for 30 min followed by 24 hours of reperfusion. Vehicle, indomethacin, or SW033291 were intraperitoneally administered three times at 1 hour before, immediately after, and 12 hours after IRI. Renal function, histological changes, and renal blood flow were compared and the relevant parameters of oxidative stress and inflammation were detected. Results Prophylactic administration of SW033291 significantly increased renal tissue PGE2 levels and increased post-AKI renal blood flow and renal arteriole area. In parallel, prophylactic SW033291 decreased post-AKI histologic injury score and tubular apoptosis and markedly reduced biomarkers of renal injury that included BUN, creatinine, NGAL and KIM-1. Prophylactic SW033291 also reduced post-AKI induction of proinflammatory cytokines, high mobility group box 1 (HMGB1), and malondialdehyde (MDA). Protective effects of SW033291 were mediated by PGE2 signaling as they could be blocked by pharmacologic inhibition of PGE2 synthesis or of the EP4 type PGE2 receptor. Consistent with activation of PGE2 signaling, SW033291 induced renal levels of both EP4 and of cyclic adenosine monophosphate (cAMP), along with other vasodilatory effectors including AMP, adenosine, and the adenosine A2A receptor (A2A). Protective effects of SW0333291 could largely be achieved with a single prophylactic dose of the drug. Conclusion Inhibiting 15-PGDH may thus represent a novel strategy for prophylaxis of ischemic AKI in multiple clinical settings, including renal transplantation and cardiovascular surgery.

scholarly journals Inhibition of 15-PGDH prevents ischemic renal injury by the PGE2/EP4 signaling pathway mediating vasodilation, increased renal blood flow, and increased adenosine/A2A receptors

2020 ◽  
Vol 319 (6) ◽  
pp. F1054-F1066
Author(s):  
Hye Jung Kim ◽  
Sun-Hee Kim ◽  
Minjung Kim ◽  
HyungJoo Baik ◽  
Seok Ju Park ◽  
...  
Keyword(s):  
Blood Flow ◽  
Renal Blood Flow ◽  
Renal Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
High Mobility ◽  
Kidney Injury ◽  
Clinical Problem ◽  
Protective Effects

In the present study, we demonstrated the marked activity of SW033291, an inhibitor of 15-hydoxyprostaglandin dehydrogenase (15-PGDH), in preventing acute kidney injury (AKI) in a murine model of ischemia-reperfusion injury. AKI due to ischemic injury represents a significant clinical problem. PGE2 is vasodilatory in the kidney, but it is rapidly degraded in vivo due to catabolism by 15-PGDH. We investigated the potential of SW033291, a potent and specific 15-PGDH inhibitor, as prophylactic treatment for ischemic AKI. Prophylactic administration of SW033291 significantly increased renal tissue PGE2 levels and increased post-AKI renal blood flow and renal arteriole area. In parallel, prophylactic SW033291 decreased post-AKI renal morphology injury scores and tubular apoptosis and markedly reduced biomarkers of renal injury that included blood urea nitrogen, creatinine, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1. Prophylactic SW033291 also reduced post-AKI induction of proinflammatory cytokines, high-mobility group box 1, and malondialdehyde. Protective effects of SW033291 were mediated by PGE2 signaling, as they could be blocked by pharmacological inhibition of PGE2 synthesis. Consistent with activation of PGE2 signaling, SW033291 induced renal levels of both EP4 receptors and cAMP, along with other vasodilatory effectors, including AMP, adenosine, and the adenosine A2A receptor. The protective effects of SW0333291 could largely be achieved with a single prophylactic dose of the drug. Inhibition of 15-PGDH may thus represent a novel strategy for prophylaxis of ischemic AKI in multiple clinical settings, including renal transplantation and cardiovascular surgery.

scholarly journals Protective effects of adenosine A2A receptor agonist in ventilator-induced lung injury in rats

2009 ◽  
Vol 37 (7) ◽  
pp. 2235-2241 ◽  
Author(s):  
Chin-Ming Chen ◽  
Oscar Penuelas ◽  
Kieran Quinn ◽  
Kuo-Chen Cheng ◽  
Chien-Feng Li ◽  
...  
Keyword(s):  
Lung Injury ◽  
Receptor Agonist ◽  
Adenosine A2a Receptor ◽  
Protective Effects ◽  
Ventilator Induced Lung Injury ◽  
A2a Receptor ◽  
Adenosine A2a

Parkinsonism-like disease induced by rotenone in rats: Treatment role of curcumin, dopamine agonist and adenosine A2A receptor antagonist

2021 ◽  
Vol 14 ◽  
Author(s):  
Asmaa Fathy Aboul Naser ◽  
Wessam Magdi Aziz ◽  
Yomna Rashad Ahmed ◽  
Wagdy Khalil Bassaly Khalil ◽  
Manal Abdel Aziz Hamed
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Inflammatory Mediator ◽  
Adenosine A2a Receptor ◽  
Control Group ◽  
A2a Receptor ◽  
Adenosine A2a

Background: Parkinsonism is a neurodegenerative disorder that affects elderly people worldwide. Methods: Curcumin, adenosine A2AR antagonist (ZM241385) and Sinemet® (L-dopa) were evaluated against Parkinson’s disease (PD) induced by rotenone in rats and comparativelyrelatively compared with our previous study on mice model. Results: Rats injected with rotenone showed severe alterations in adenosine A2A receptor gene expression, oxidative stress markers, inflammatory mediator, energetic indices, apoptotic marker and DNA fragmentation levels as compare with the control group. Treatments with curcumin, ZM241385, and Sinemet® restored all the selected parameters. The brain histopathological features of cerebellum regions confirmed our results. By comparing our results with the previous results on mice, we noticed that mice respond to rotenone toxicity and treatments more than rats regarding to behavioral observation, A2AR gene expression, neurotransmitter levels, inflammatory mediator and apoptotic markers, while rats showed higher response to treatments regarding to oxidative stress and energetic indices. Conclusion: Curcumin succeeded to attenuate the severe effects of Parkinson’s disease in rat model and can be consider as a potential dietary supplement. Adenosine A2AR antagonist has almost the same pattern of improvement as Sinemet® and may be considered as a promising therapy against PD. By comparing the role of animal species in response to PD symptoms and treatments, our previous report on mice explore the response of mice to rotenone toxicity than rats, while rats showed higher response to treatments. Therefore, no animal model can perfectly recapitulate all the pathologies of PD.

Postischemic renal injury is mediated by neutrophils and leukotrienes

1989 ◽  
Vol 256 (5) ◽  
pp. F794-F802 ◽  
Author(s):  
J. M. Klausner ◽  
I. S. Paterson ◽  
G. Goldman ◽  
L. Kobzik ◽  
C. Rodzen ◽  
...  
Keyword(s):  
Blood Flow ◽  
Renal Blood Flow ◽  
Renal Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Rabbit Antiserum ◽  
Artery Blood Flow ◽  
Tubular Necrosis ◽  
Muscle Ischemia ◽  
Neutrophil Depletion

Neutrophils have been implicated as central mediators in myocardial and skeletal muscle ischemia-reperfusion injury. This study tests whether these cellular elements and the chemoattractant leukotriene (LTB4) play a role in postischemic renal failure. Anesthetized rats underwent 45 min of left renal pedicle clamping. Five minutes after reperfusion, LTB4 levels were elevated to 1.42 ng/ml (P less than 0.05); thromboxane (Tx)B2 was 2,840 pg/ml, higher than 503 pg/ml in sham controls (P less than 0.05); renal artery blood flow was 67% of preclamping values at 1 min of reperfusion compared with 111% in sham (P less than 0.05). At 24 h, creatinine levels were 4.6 mg/dl (P less than 0.05). At 24 h, creatinine levels were 4.6 mg/dl (P less than 0.05); histology showed acute tubular necrosis (ATN). Neutrophil depletion by rabbit antiserum (n = 8) led during reperfusion to reduced LTB4 and TxB2 levels, 1.04 ng/ml and 1.043 pg/ml (P less than 0.05); increased renal blood flow of 174% (P less than 0.05); reduced creatinine levels of 1.8 mg/dl (P less than 0.05); and limited ATN. Pretreatment with diethycarbamazine prevented the increases in LTB4 and TxB2 (P less than 0.05), increased renal blood flow (P less than 0.05), minimized creatinine increase to 1.7 mg/dl (P less than 0.05), and reduced ATN. These data indicate that neutrophils and LTB4 play a role in ischemia-induced Tx synthesis and mediate postischemic renal injury.

Adenosine A2A Receptor Agonist Improves Cardiac Dysfunction From Pulmonary Ischemia-Reperfusion Injury

2005 ◽  
Vol 79 (4) ◽  
pp. 1189-1195 ◽  
Author(s):  
T. Brett Reece ◽  
Victor E. Laubach ◽  
Curtis G. Tribble ◽  
Thomas S. Maxey ◽  
Peter I. Ellman ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Cardiac Dysfunction ◽  
Receptor Agonist ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Adenosine A2a Receptor ◽  
A2a Receptor ◽  
Adenosine A2a ◽  
Pulmonary Ischemia

scholarly journals Adenosine A2a Receptor Stimulation Attenuates Ischemia-Reperfusion Injury and Improves Survival in A Porcine Model of DCD Liver Transplantation

2020 ◽  
Vol 21 (18) ◽  
pp. 6747
Author(s):  
Zoltan Czigany ◽  
Eve Christiana Craigie ◽  
Georg Lurje ◽  
Shaowei Song ◽  
Kei Yonezawa ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Adenosine A2a Receptor ◽  
Large Animal Model ◽  
Large Animal ◽  
Receptor Stimulation ◽  
A2a Receptor ◽  
Htk Solution ◽  
Adenosine A2a

Orthotopic liver transplantation (OLT) using allografts from donation after circulatory death (DCD) is potentially associated with compromised clinical outcomes due to ischemia-reperfusion injury (IRI)-induced organ damage and graft-related complications. The aim of this study was to provide in vivo data on the effects of adenosine A2a receptor stimulation in a clinically relevant large animal model of DCD liver transplantation. Cardiac arrest was induced in German Landrace pigs (n = 10; 20–25 kg). After 30 min of warm ischemia, the donor liver was retrieved following a cold flush with 3 L of histidine-tryptophan-ketoglutarate-HTK solution. Animals of the treatment group (n = 5/group) received a standard dose of the selective adenosine receptor agonist CGS 21680 added to the cold flush. All grafts were stored for 4.5 h at 4 °C in HTK-solution before OLT. Hepatocellular injury, apoptosis, protein kinase A-PKA activity, graft microcirculation, liver function, and animal survival were assessed. Compared to untreated livers, adenosine A2a receptor stimulation resulted in improved tissue microcirculation (103% ± 5% vs. 38% ± 4% compared to baseline; p < 0.05), accelerated functional recovery of the graft (indocyanine green-plasma disappearance rate (ICG-PDR) of 75% ± 18% vs. 40% ± 30% after 3 h), increased PKA activity ratio (56% ± 3% vs. 32% ± 3%; p < 0.001 after 1 h), and consequently reduced tissue necrosis and apoptosis. The potent protective effects were clinically manifested in significantly improved survival in the treatment group after 72 h (100% vs. 40%; p = 0.04). The ex vivo administration of adenosine A2a receptor agonist during the back-table flush mitigates IRI-mediated tissue damage and improves functional graft recovery and survival in a large animal model of DCD liver transplantation.

scholarly journals Role of adenosine A2a receptor in regulation of cerebral blood flow (CBF) during induced hypotension

2008 ◽  
Vol 22 (S1) ◽  
Author(s):  
Yoshikazu Kusano ◽  
Grzegorz Miekisiak ◽  
Tobias Kulik ◽  
Adam Sandler ◽  
Richard H. Winn
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Adenosine A2a Receptor ◽  
Induced Hypotension ◽  
A2a Receptor ◽  
Adenosine A2a

scholarly journals METABOLIC CHANGES INDUCED BY BUSHENHUOXUE GRANULES ON STRIATUM AND SUBSTANTIA NIGRA IN A RAT MODEL OF PARKINSON’S DISEASE

2017 ◽  
Vol 15 (1) ◽  
pp. 1
Author(s):  
Yunxia Guo ◽  
Junxiu Zhang ◽  
Shaodan Li ◽  
Yin Zhang ◽  
Yi Liu ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Normal Control Group ◽  
Adenosine A2a Receptor ◽  
Rat Striatum ◽  
Control Group ◽  
Control Groups ◽  
A2a Receptor ◽  
Adenosine A2a

Background: Parkinson’s disease is a neurodegenerative disease, while its mechanism is still unclear. Long-term levodopa-based treatment leads to decreased response or loss of response, as well as severe side effects. Our previous study has proved that Bushenhuoxue Granules have effects on Parkinson’s disease, but the underlying mechanism is still need to be explored. Our research is to investigate the mechanisms of Bushenhuoxue Granules on Parkinson’s disease (PD) by examining changes in the expression of the adenosine A2A receptor、vesicular monoamine transporter 2 (VMAT2)、divalent metal transporter 1（DMT1） and nuclear factor E2 related (Nrf2) in a rat model of Parkinson’s disease (PD) . Materials and Methods: Changes in the apomorphine (APO)-induced rotational behavior of rats were observed after treatment. Immunofluorescence and immunohistochemistry were performed to investigate changes in adenosine A2A receptor 、VMAT2、DMT1 and Nrf2 expression in the rat striatum and substantia nigra. Results: Rotations after treatment were199.11 ± 27.16, which significantly decreased compared with that before treatment ( 273.0 ± 44.61, p < 0.01). Adenosine A2A receptor expression in the striatum was 3.10 ± 0.34 significantly increased in the model group and decreased in the normal control group, whereas the expression level in the Bushenhuoxue group was 1.13 ± 0.23,p < 0.05 between the two control groups. No adenosine A2A receptor expression was observed in the substantia nigra. VMAT2 expression in the rat striatum was 23.20 ± 2.68 and substantia nigra was 15.98 ± 0.70 increased in the normal control group. They were 8.99 ± 0.48 in the rat striatum and 8.45 ± 0.59 substantia nigra significantly decreased in the model control group, whereas the expression level in the Bushenhuoxue group was 15.36 ± 0.89 in the rat striatum and 11.69 ± 1.17 in the rat substantia nigra (p < 0.05), also between the two control groups. DMT1 expression in the rat striatum was 3.30 ± 0.30 and substantia nigra was 6.56 ± 0.64 decreased in the normal control group. They were 7.92 ± 0.52 in the rat striatum and 12.76 ± 0.86 substantia nigra significantly increased in the model control group, whereas the expression level in the Bushenhuoxue group was 6.17 ± 0.27 in the rat striatum and 9.13 ± 0.44 in the rat substantia nigra (p < 0.05), also between the two control groups. Nrf2 expression in the rat striatum was 7.90 ± 0.29 and substantia nigra was 15.22 ± 1.22 increased in the normal control group. They were 3.09 ± 0.43 in the rat striatum and 8.57 ± 0.54 substantia nigra significantly decreased in the model control group, whereas the expression level in the Bushenhuoxue group was 5.00 ± 0.34 in the rat striatum and 12.46 ± 0.62 in the rat substantia nigra (p< 0.05), also between the two control groups. Conclusion: Bushenhuoxue Granules significantly improved the rotational behavior of PD’s rats, decreased adenosine A2A receptor expression, and increased VMAT2 expression; decreased DMT1 expression, and increased Nfr2 expression.

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