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Effect of renal dysfunction to inflammation in brain and hemostasis in blood

Other Titles
 신기능저하가 뇌의 염증반응 및 혈액 내 지혈기전에 미치는 영향 
Authors
 송태진 
Department
 Dept. of Neurology (신경과학교실) 
Issue Date
2017
Description
Dept. of Medicine/박사
Abstract
Background: Pathophysiologic mechanisms of inflammatory reactions of the brain in chronic renal failure (CRF) have not been completely understood. Moreover, several abnormalities in hemostasis and coagulation have been suggested in CRF. This study aimed to investigate whether there are changes in the expression of high-mobility group box 1(HMGB1) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), which are related with inflammation, in brain after 5/6 nephrectomy of rats. In addition, this study compared the process of thrombus formation between rats with early stage of CRF and those with normal kidney function. Methods: For evaluating neuroinflammation, male Sprague–Dawley rats were used in all experiments (control for acute kidney injury (AKI): n = 10, control for CRF: n = 10, AKI: n = 10, CRF: n = 10). For investigating thrombus formation, a total of 30 rats were used (control: n = 15 [5 for FeCl3-induced arterial thrombosis model, 5 for rotational thromboelastometry (ROTEM), and 5 for impedance platelet aggregometry (IPA)], CRF: n = 15 [5 for FeCl3-induced arterial thrombosis model, 5 for ROTEM, and 5 for IPA]). AKI model was prepared by clamping bilateral renal artery for 45 minutes followed by reperfusion. For CRF model, 5/6 nephrectomy was done. The brain and kidney tissues were harvested 6 hours after inducing AKI and 4 weeks after inducing CRF. Tissues were processed for immunoblot analysis, immunohistochemistry, and TUNEL staining. FeCl3-induced thrombosis in carotid artery was used to assess thrombus formation. Whole blood clot formation was evaluated in extrinsic pathway rotational thromboelastometry (EXTEM) with recombinant tissue factor for extrinsic pathway and intrinsic pathway rotational thromboelastometry (INTEM) with contact activation for intrinsic pathway using ROTEM. Platelet aggregation was assessed using IPA. Results: In immunoblot, HMGB1 was upregulated in brains of the both AKI and CRF groups (p = 0.001). The expression of NF-κB was significantly increased in the CRF group (p = 0.001), but not in the AKI group (p = 0.999) comparing with that of the control group. Immunohistochemistry demonstrated the increases of nuclear staining for HMGB1 and NF-κB in frontal cortex and hippocampus of the CRF group comparing with those of the AKI or the control group (p = 0.001). In addition, apoptotic cell death in the CRF group was identified by TUNEL staining. In experiments of FeCl3-induced thrombosis of the carotid artery, time to mean blood flow reduction (10% and 50%) by thrombotic occlusion was shorter in the CRF group than in the control group (10%: 0.50 ± 0.02 vs. 0.70 ± 0.02 minutes, p = 0.001) (50%: 1.91±0.25 vs. 2.54 ± 0.36 minutes, p = 0.014). On histology, the maximal length of thrombus was larger in the CRF group than the control group (1070.8 ± 9.4 vs. 995.2 ± 8.6 μm, p = 0.001). In EXTEM, the CRF group showed faster clot initiation (clotting time, 0.98 ± 0.12 vs. 1.46 ± 0.08 minutes, p = 0.032) and increased clot growth kinetics (α angle, 84.8 ± 0.2 vs. 82.0 ± 0.6, p = 0.008) than the control group. Maximal platelet aggregation rate was higher in the CRF group than the control group (58.2 ± 0.2 vs. 44.6 ± 1.2 %, p = 0.006). Conclusions: Our study showed that CRF may be associated with increased expression of HMGB1 and NF-κB in the brain. These results suggest that CRF would be related to inflammatory reaction of brain via HMGB1 and NF-κB pathways. Furthermore, our study demonstrated that thrombogenic process was increased in CRF of rats. Activated extrinsic coagulation pathway may play an important role for increased thrombogenic process in the early stage of CRF. 배경: 만성 신부전 상태에서 뇌에 염증반응이 발생하는 병리학적 기전은 아직 잘 알려진 바가 없다. 또한, 현재까지 만성 신부전 상태에서 지혈기전의 이상, 특히 혈전의 생성에 대해 연구는 미흡한 상황이다. 본 연구자들은 인체의 염증반응에 중요한 부분을 담당한다고 알려져 있는 high-mobility group box 1 (HMGB1)과 nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)이 5/6 신장절제를 시행 후 4주 경과한 쥐의 뇌에서 어떻게 변화하는지를 확인하고자 하였다....
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Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Neurology (신경과학교실) > 3. Dissertation
Yonsei Authors
Song, Tae Jin(송태진)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/154841
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