Glycogen Synthase Kinase-3β Inhibitor Attenuates Renal Damage Through Regulating Antioxidant and Anti-inflammation in Rat Kidney Transplant With Cold Ischemia Reperfusion

2019 ◽  
Vol 51 (6) ◽  
pp. 2066-2070 ◽  
Author(s):  
Bo Hu ◽  
Jie Tang ◽  
Yi Zhang ◽  
Zhenyi Ma ◽  
Yungang Shan ◽  
...  
Keyword(s):  
Kidney Transplant ◽  
Renal Damage ◽  
Glycogen Synthase ◽  
Rat Kidney ◽  
Ischemia Reperfusion ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Cold Ischemia ◽  
Anti Inflammation

Inhibition of Glycogen Synthase Kinase-3β Attenuates Organ Injury and Dysfunction Associated With Liver Ischemia-Reperfusion and Thermal Injury in the Rat

Shock ◽  
2015 ◽  
Vol 43 (4) ◽  
pp. 369-378 ◽  
Author(s):  
Joao Rocha ◽  
Maria-Eduardo Figueira ◽  
Andreia Barateiro ◽  
Adelaide Fernandes ◽  
Dora Brites ◽  
...  
Keyword(s):  
Thermal Injury ◽  
Glycogen Synthase ◽  
Ischemia Reperfusion ◽  
Glycogen Synthase Kinase ◽  
Organ Injury ◽  
Liver Ischemia ◽  
Glycogen Synthase Kinase 3Β

scholarly journals Aldose reductase modulates cardiac glycogen synthase kinase-3β phosphorylation during ischemia-reperfusion

2012 ◽  
Vol 303 (3) ◽  
pp. H297-H308 ◽  
Author(s):  
Mariane Abdillahi ◽  
Radha Ananthakrishnan ◽  
Srinivasan Vedantham ◽  
Linshan Shang ◽  
Zhengbin Zhu ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Aldose Reductase ◽  
Glycogen Synthase ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Cardiac Cells ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Apoptotic Markers ◽  
Ldh Release

Earlier studies have demonstrated that aldose reductase (AR) plays a key role in mediating ischemia-reperfusion (I/R) injury. Our objective was to investigate if AR mediates I/R injury by influencing phosphorylation of glycogen synthase kinase-3β (p-GSK3β). To investigate this issue, we used three separate models to study the effects of stress injury on the heart. Hearts isolated from wild-type (WT), human expressing AR transgenic (ARTg), and AR knockout (ARKO) mice were perfused with/without GSK3β inhibitors (SB-216763 and LiCl) and subjected to I/R. Ad-human AR (Ad-hAR)-expressing HL-1 cardiac cells were exposed to hypoxia (0.5% O2) and reoxygenation (20.9% O2) conditions. I/R in a murine model of transient occlusion and reperfusion of the left anterior descending coronary artery (LAD) was used to study if p-GSK3β was affected through increased AR flux. Lactate dehydrogenase (LDH) release and left ventricular developed pressure (LVDP) were measured. LVDP was decreased in hearts from ARTg mice compared with WT and ARKO after I/R, whereas LDH release and apoptotic markers were increased ( P < 0.05). p-GSK3β was decreased in ARTg hearts compared with WT and ARKO ( P < 0.05). In ARKO, p-GSK3β and apoptotic markers were decreased compared with WT ( P < 0.05). WT and ARTg hearts perfused with GSK3β inhibitors improved p-GSK3β expression and LVDP and exhibited decreased LDH release, apoptosis, and mitochondrial pore opening ( P < 0.05). Ad-hAR-expressing HL-1 cardiac cells, exposed to hypoxia (0.5% O2) and reoxygenation (20.9% O2), had greater LDH release compared with control HL-1 cells ( P < 0.05). p-GSK3β was decreased and correlated with increased apoptotic markers in Ad-hAR HL-1 cells ( P < 0.05). Treatment with phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) inhibitor increased injury demonstrated by increased LDH release in ARTg, WT, and ARKO hearts and in Ad-hAR-expressing HL-1 cells. Cells treated with protein kinase C (PKC) α/β inhibitor displayed significant increases in p-Akt and p-GSK3β expression, and resulted in decreased LDH release. In summary, AR mediates changes in p-GSK3β, in part, via PKCα/β and Akt during I/R.

Tissue injury after lithium treatment in human and rat postnatal kidney involves glycogen synthase kinase-3β-positive epithelium

2012 ◽  
Vol 302 (4) ◽  
pp. F455-F465 ◽  
Author(s):  
Gitte Kjaersgaard ◽  
Kirsten Madsen ◽  
Niels Marcussen ◽  
Sten Christensen ◽  
Steen Walter ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Rat Kidney ◽  
Lithium Treatment ◽  
Glycogen Synthase Kinase ◽  
Nuclear Antigen ◽  
Thick Ascending Limb ◽  
Glycogen Synthase Kinase 3Β ◽  
Distal Nephron ◽  
Collecting Ducts ◽  
Gsk 3Β

It was hypothesized that lithium causes accelerated and permanent injury to the postnatally developing kidney through entry into epithelial cells of the distal nephron and inhibition of glycogen synthase kinase-3β (GSK-3β). GSK-3β immunoreactivity was associated with glomeruli, the thick ascending limb of Henle's loop, and collecting ducts in the developing and adult human and rat kidney. In rats, the abundance of inactive, phosphorylated GSK-3β (pGSK-3β) protein decreased during postnatal development. After feeding of dams with litters lithium [50 mmol Li/kg chow, postnatal (P) days 7–28], the offspring showed plasma lithium concentration of 1.0 mmol/l. Kidneys from lithium-treated rat pups exhibited dilated distal nephron segments with microcysts. Stereological analysis showed reduced cortex and outer medullary volumes. Lithium increased pGSK-3β and the proliferation marker proliferating cell nuclear antigen (PCNA) protein abundances in the cortex and medulla. After lithium treatment, pGSK-3β-immunopositive cells exhibited restricted distribution and were associated primarily with subsets of cells in dilated and microcystic segments of cortical collecting ducts. After 6 wk of lithium discontinuation, adult rats exhibited attenuated urine concentration capacity and diminished outer medullary volume. Histological sections of two nephrectomy samples and a biopsy from three long-term lithium-treated patients showed multiple cortical microcysts that originated from normally appearing tubules. Microcysts were lined by a cuboidal PCNA-, GSK-3β-, and pGSK-3β-immunopositive epithelium. The postnatal rat kidney may serve as an experimental model for the study of lithium-induced human kidney injury. The data are compatible with a causal relationship between epithelial entry of lithium into cells of the aldosterone-sensitive distal nephron, inactivation of GSK-3β, proliferation, and microcysts.

scholarly journals Involvement of glycogen synthase kinase-3β in liver ischemic conditioning induced cardioprotection against myocardial ischemia and reperfusion injury in rats

2017 ◽  
Vol 122 (5) ◽  
pp. 1095-1105 ◽  
Author(s):  
Shuai Yang ◽  
Geoffrey W. Abbott ◽  
Wei Dong Gao ◽  
Jin Liu ◽  
Chaozhi Luo ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Ischemia Reperfusion ◽  
Glycogen Synthase Kinase ◽  
Ischemia And Reperfusion ◽  
Glycogen Synthase Kinase 3Β ◽  
Ischemia And Reperfusion Injury ◽  
Remote Ischemic Conditioning ◽  
Ischemic Conditioning ◽  
Dependent Cell ◽  
Gsk 3Β

Remote ischemic conditioning has been convincingly shown to render the myocardium resistant to a subsequent more severe sustained episode of ischemia. Compared with other organs, little is known regarding the effect of transient liver ischemic conditioning. We proposed the existence of cardioprotection induced by remote liver conditioning. Male Sprague-Dawley rats were divided into sham-operated control (no further hepatic intervention) and remote liver ischemic conditioning groups. For liver ischemic conditioning, three cycles of 5 min of liver ischemia-reperfusion stimuli were conducted before-(liver preconditioning), post-myocardial ischemia (liver postconditioning), or in combination of both (liver preconditioning + liver postconditioning). Rats were exposed to 45 min of left anterior descending coronary artery occlusion, followed by 3 h of reperfusion thereafter. ECG and hemodynamics were measured throughout the experiment. The coronary artery was reoccluded at the end of reperfusion for infarct size determination. Blood samples were taken for serum lactate dehydrogenase and creatine kinase-MB test. Heart tissues were taken for apoptosis measurements and Western blotting. Our data demonstrate that liver ischemic preconditioning, postconditioning, or a combination of both, offered strong cardioprotection, as evidenced by reduction in infarct size and cardiac tissue damage, recovery of cardiac function, and inhibition of apoptosis after ischemia-reperfusion. Moreover, liver ischemic conditioning increased cardiac (not hepatic) glycogen synthase kinase-3β (GSK-3β) phosphorylation. Accordingly, inhibition of GSK-3β mimicked the cardioprotective action of liver conditioning. These results demonstrate that remote liver ischemic conditioning protected the heart against ischemia and reperfusion injury via GSK-3β-dependent cell-survival signaling pathway. NEW & NOTEWORTHY Remote ischemic conditioning protects hearts against ischemia and reperfusion (I/R) injury. However, it is unclear whether ischemic conditioning of visceral organs such as the liver, the largest metabolic organ in the body, can produce cardioprotection. This is the first study to show the cardioprotective effect of remote liver ischemic conditioning in a rat model of myocardial I/R injury. We also, for the first time, demonstrated these protective properties are associated with glycogen synthase kinase-3β-dependent cell-survival signaling pathway.

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