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TNF-α Induces Endothelial Dysfunction via PKC-ζ-dependent NADPH Oxidase Activation

Journal of Huazhong University of Science and Technology(Medical Sciences) 2012年第5期32卷 642-647页

作者：黄毅严丽容松 hermann haller Torsten Kirch Department of Nephrology Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Department of Nephrology Hannover Medical School

Endothelial dysfunction is implicated in a variety of cardiovascular diseases although the detailed mechanisms are not yet completely understood. A relationship has been suggested to exist between inflammation and endothelial dysfunction. TNF-α serves as one of the most important pro-inflammatory cytokines. The main objectives of the present study were to explore the effect of PKC-ζ on TNF-α-impaired endothelial function as well as the underlying mechanisms. Acetylcho-line-induced endothelium-dependent vasodilation of mouse thoracic aorta stimulated by TNF-α was initially determined. PKC-ζ deficient mice and the specific inhibitor of NADPH oxidase were respectively applied to elucidate their roles in TNF-α-induced endothelial dysfunction. In vitro superoxide generation in HAECs was detected by DHE staining after administration of TNF-α. Meanwhile, the regulatory p47phox subunit of NADPH oxidase was evaluated by Western blotting and RT-PCR. The results showed that TNF-α conspicuously impaired endothelium-dependent vasodilation and the impairment was attenuated by either depleting PKC-ζ or inhibiting NADPH oxidase. In vitro TNF-α increased superoxide production and p47phox expression in HAECs, and such increases could be ameliorated by the specific PKC-ζ inhibitor. Our findings suggest that superoxide over-production triggered by PKC-ζ-dependent NADPH oxidase activation contributes to TNF-α-induced endothelial dysfunction.

关键词： endothelial dysfunction TNF-α PKC-ζ NADPH oxidase

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C-X3-C motif chemokine ligand 1/receptor 1 regulates the M1 polarization and chemotaxis of macrophages after hypoxia/reoxygenation injury

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Chronic Diseases and Translational Medicine 2021年第4期7卷 254-265页

作者： Shuiming Guo Lei Dong Junhua Li Yuetao Chen Ying Yao Rui Zeng Nelli Shushakova hermann haller Gang Xu Song Rong Department of Nephrology Division of Internal MedicineTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei 430030China Department of Respiratory Division of Internal MedicineTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei 430030China Department of Nephrology Hannover Medical SchoolHannover 30625Germany

Background:Macrophages play an important role in renal ischemia reperfusion injury,but the functional changes of macrophages under hypoxia/reoxygenation and the related mechanism are unclear and need to be further clarified.Methods:The effects of hypoxia/reoxygenation on functional characteristics of RAW264.7 macrophages were analyzed through the protein expression detection of pro-inflammatory factors TNF-αand CD80,anti-inflammatory factors ARG-1 and CD206.The functional implications of C-X3-C motif chemokine receptor 1(CX3CR1)down-regulation in hypoxic macrophages were explored using small interfering RNA technology.Significance was assessed by the parametrict-test or nonparametric Mann-Whitney test for two group comparisons,and a one-way ANOVA or the Kruskal-Wallis test for multiple group comparisons.Results:Hypoxia/reoxygenation significantly increased the protein expression of M1-related pro-inflammatory factors TNF-α,CD80 and chemokine C-X3-C motif chemokine ligand 1(CX3CL1)/CX3CR1 and inhibited the protein expression of M2-related anti-inflammatory factors ARG-1 and CD206 in a time-dependent manner in RAW264.7 cells.However,the silencing of CX3CR1 in RAW264.7 cells using specific CX3CR1-siRNA,significantly attenuated the increase in protein expression of TNF-α(P<0.05)and CD80(P<0.01)and the inhibition of ARG-1(P<0.01)and CD206(P<0.01)induced by hypoxia/reoxygenation.In addition,we also found that hypoxia/reoxygenation could significantly enhance the migration(2.2-fold,P<0.01)and adhesion capacity(1.5-fold,P<0.01)of RAW264.7 macrophages compared with the control group,and CX3CR1-siRNA had an inhibitory role(40%and 20%reduction,respectively).For elucidating the mechanism,we showed that the phosphorylation levels of ERK(P<0.01)and the p65 subunit of NF-κB(P<0.01)of the RAW264.7 cells in the hypoxic/reoxygenation group were significantly increased,which could be attenuated by down-regulation of CX3CR1 expression(P<0.01,both).ERK inhibitors also significantly blocked the effects of hypoxic/reoxygenation on the

关键词： Macrophages Hypoxia/Reoxygenation C-X3-C motif chemokine ligand 1/receptor 1 Phenotypic polarization

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Telomere shortening in patients on long-term hemodialysis

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Chronic Diseases and Translational Medicine 2021年第4期7卷 266-275页

作者： Yucheng Wang Siyu Chen Shi Feng Cuili Wang Hong Jiang Song Rong haller hermann Jianghua Chen Ping Zhang Kidney Disease Center The First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouZhejiang 310003China Key Laboratory of Nephropathy HangzhouZhejiang 310003China Kidney Disease Immunology Laboratory The Third-Grade LaboratoryState Administration of Traditional Chinese Medicine of ChinaHangzhouZhejiang 310003China Key Laboratory of Multiple Organ Transplantation Ministry of Health of ChinaHangzhouZhejiang 310003China Institute of Nephropathy Zhejiang UniversityHangzhouZhejiang 310003China Clinic for Kidney and Hypertension Diseases Hannover Medical SchoolLower Saxony30625Germany

Background:Leukocyte telomere length shortening is a characteristic of premature senescence,a process that can be accelerated by oxidative stress.In general,patients with end-stage renal disease undergoing regular hemodialysis(HD)are repeatedly exposed to oxidative stress.Patients undergoing HD tend to have cardiovascular diseases associated with oxidative stress and inflammation.Therefore,we assumed that telomere length is associated with HD vintage and the degree of vascular calcification.Methods:A total of 144 patients undergoing regular HD before kidney transplantation and 62 patients on hemodialysis,but not undergoing kidney transplantation,were enrolled.We measured common laboratory values,such as calcium,phosphate,and hemoglobin levels,and assessed the degree of vascular calcification in the patients.The leukocyte telomere length was measured using reverse transcription polymerase chain reaction,and Spearman correlation was used for correlation analysis.Results:The leukocyte telomere length was negatively associated with age(rho=-0.306,P<0.01);it was shorter in middle-aged patients than in young patients(13.48±4.80 vs.15.86±4.51,P<0.01).The telomere length was significantly different among patients aged 52-74 years in groups with different HD vintages.Additionally,the telomere length was positively associated with serum hemoglobin(Hb)levels in all patients(rho=0.290,P<0.01).There was a significant difference among patients divided into three groups according to the degree of anemia(17.09±5.64 vs.14.40±4.07 vs.13.99±3.95,P<0.01).Further,a significant difference was observed in the telomere length among patients with different degrees of vascular calcification(16.79±4.91 vs.13.61±2.82 vs.14.62±3.63 vs.10.71±3.74,P<0.01).The telomere length was shorter in the patients on hemodialysis who did not receive a kidney transplant than in the surgical patients(8.12±1.83 vs.14.33±4.63,P<0.01).Conclusion:This study demonstrated that the telomere length was significantly correlated with HD vintage in patients of a certa

关键词： Telomere length Hemodialysis Chronic kidney disease Cardiovascular disease Hemoglobin

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Pharmacological Tie2 activation in kidney transplantation

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World Journal of Transplantation 2016年第3期6卷 573-582页

作者： Kristina Thamm Florence Njau Paul Van Slyke Daniel J Dumont Joon-Keun Park hermann haller Sascha David Department of Nephrology and Hypertension Medical School Hannover Vasomune Therapeutics Inc Biological Sciences Sunnybrook Research Institute

AIM To investigate the therapeutic potential of vasculotide(VT)- a Tie2 activating therapeutic- in kidney transplantation.METHODS We performed a murine MHC-mismatched renal transplant model(C57Bl/6 male into Balb/c female) with 60 min cold and 30 min warm ischemia time. 500 ng VT was administered i.p. to donor mice 1 h before organ removal. In addition, recipients received 500 ng VT i.p. directly and 3 d after surgery. Survival was monitored and remaining animals were sacrificed 28 d after transplantation. In this model, we analyzed:(1) organ function;(2) Kaplan-Meier survival;(3) organ damage(periodic acid Schiff staining) via semi-quantitative scoring [0-4(0 = no injury/inflammation to 4 = very severe injury/inflammation)];(4) expression of renal endothelial adhesion molecules(ICAM-1) viaimmunofluorescence(IF) staining, immunoblotting and q PCR;(5) infiltration of inflammatory cells(IF Gr-1, F4/80); and(6) fibrosis via staining of α-smooth muscle actin(αSMA), Sirius red staining and immunoblotting of SMAD3 activation.RESULTS Exogenous activation of Tie2 with VT resulted in diminished expression of peritubular and glomerular endothelial adhesion molecules. Consequently, infiltration of inflammatory cells(analyzed as ICAM-1, Gr-1 and F4/80 positive cells) was reduced in VT-treated mice compared to controls. Additionally, VT was protective against fibrogenesis after kidney transplantation. Trends towards lower serum creatinine(vehicle: 142 ± 17 μmol/L vs VT: 94 ± 23 μmol/L), urea(vehicle: 76 ± 5 mmol/L vs VT: 60 ± 8 mmol/L) and lactate dehydrogenase(vehicle: 1288 ± 383 iU vs VT: 870 ± 275 iU) were observed on day 6 after transplantation. Kaplan-Meier survival analysis showed improved survival rates in the VT-treated mice that did not reach statistical significance(27% vs 54%, P = 0.24, n = 11 per group). Exogenous activation of Tie2 via VT might reduce infiltration of inflammatory cells into renal tissue thereby protecting the transplant from early graft dysfunction potentially affecting long-term function.CONCLUS

关键词： Vasculotide Tie2 Kidney transplantation Endothelium Angiopoietin

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与安慰剂相比,沙格列汀在伴有肾功能不全的2型糖尿病患者中能改善血糖控制并且具有良好的耐受性

与安慰剂相比,沙格列汀在伴有肾功能不全的2型糖尿病患者中能改善...

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中华医学会糖尿病学分会第十六次全国学术会议

作者： Michal Nowicki Ivan Rychlik hermann haller Mark L.Warren Lisa Suchower Ingrid Gause-Nilsson Medical University LodzPoland Charles University Third School of Medicine PragueCzech Republic Medizinische Hochschule Hannover HannoverGermany

目的沙格列汀(SAXA)是一种强效、选择性的二肽基肽脢-4(DPP-4)抑制剂,在饮食和运动基础上使用可改善成人2型糖尿病(T2DM)患者的血糖控制。一项多中心、随机分组、双盲平行、安慰剂(PBO)对照的12周研究,分析了SAXA在肾功能不全的患者中...

目的沙格列汀(SAXA)是一种强效、选择性的二肽基肽脢-4(DPP-4)抑制剂,在饮食和运动基础上使用可改善成人2型糖尿病(T2DM)患者的血糖控制。一项多中心、随机分组、双盲平行、安慰剂(PBO)对照的12周研究,分析了SAXA在肾功能不全的患者中的疗效及安全性。

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与安慰剂相比,沙格列汀在伴有肾功能不全的2型糖尿病患者中能改善血糖控制并且具有良好的耐受性

与安慰剂相比,沙格列汀在伴有肾功能不全的2型糖尿病患者中能改善...

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中华医学会第十一次全国内分泌学学术会议

作者： Michal Nowicki Ivan Rychlik hermann haller Mark L.Warren Lisa Suchower Ingrid Gause-Nilsson Medical Univeristy LodzPoland Charles University Third School of Medicine PragueCzech Republic Medizinische Hochschule Hannover HannoverGermany

背景和目的:根据统计,中国糖尿病患病人数超过九千万人,每十个成年人中就有一例,是世界上糖尿病患者最多的国家。沙格列汀(SAXA)是一种强效、选择性的二肽基肽脢-4(DPP4)抑制剂,在饮食和运动基础上使用可改善成人2型糖尿病(T2DM)患者的...

背景和目的:根据统计,中国糖尿病患病人数超过九千万人,每十个成年人中就有一例,是世界上糖尿病患者最多的国家。沙格列汀(SAXA)是一种强效、选择性的二肽基肽脢-4(DPP4)抑制剂,在饮食和运动基础上使用可改善成人2型糖尿病(T2DM)患者的血糖控制。一项多中心、随机分组、双盲平行、安慰剂(PBO)对照的12周研究,分析了SAXA在肾功能不全的患者中的疗效及安全性。

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来源： cnki会议评论

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