AIM To study hepatic vasoconstriction and glucose release induced by angiotensin(Ang)Ⅱ or Epi in rats with pharmacological hypertension and spontaneously hypertensive rat(SHR).METHODS Isolated liver perfusion was per...AIM To study hepatic vasoconstriction and glucose release induced by angiotensin(Ang)Ⅱ or Epi in rats with pharmacological hypertension and spontaneously hypertensive rat(SHR).METHODS Isolated liver perfusion was performed following portal vein and vena cava cannulation; AngⅡ or epinephrine(Epi) was injected in bolus and portal pressure monitored; glucose release was measured in perfusate aliquots. RESULTS The portal hypertensive response(PHR) and the glucose release induced by AngⅡ of L-NAME were similar to normal rats(WIS). On the other hand, the PHR inducedby Epi in L-NAME was higher whereas the glucose release was lower compared to WIS. Despite the similar glycogen content, glucose release induced by AngⅡ was lower in SHR compared to Wistar-Kyoto rats although both PHR and glucose release induced by Epi in were similar. CONCLUSION AngⅡ and Epi responses are altered in different ways in these hypertension models. Our results suggest that inhibition of NO production seems to be involved in the hepatic effects induced by Epi but not by AngⅡ; the diminished glucose release induced by AngⅡ in SHR is not related to glycogen content.展开更多
The angiotensin-converting enzyme(ACE)inhibitory peptide NCW derived from Mizuhopecten yessoensis has been demonstrated to have significant in vivo anti-hypertensive effects,however,its anti-hypertensive mechanism is ...The angiotensin-converting enzyme(ACE)inhibitory peptide NCW derived from Mizuhopecten yessoensis has been demonstrated to have significant in vivo anti-hypertensive effects,however,its anti-hypertensive mechanism is still not fully clarified.This study established a UPLC-Q-TRAP-MS/MS-based widely targeted kidney metabolomics approach to explore the changes of kidney metabolic profiles and to clarify the antihypertensive mechanism of peptide NCW in spontaneously hypertensive rats(SHRs).Multivariate statistical analysis indicated that the kidney metabolic profiles were clearly separated between the SHR-NCW and SHRUntreated groups.A total of 85 metabolites were differentially regulated,and 16 metabolites were identified as potential kidney biomarkers,e.g.,3-hydroxybutyrate,malonic acid,deoxycytidine,and L-aspartic acid.The peptide NCW might regulate kidney metabolic disorder of SHRs to alleviate hypertension by suppressing inflammation and improving nitric oxide production under the regulation of linoleic acid metabolism,folate related pathways,synthesis and degradation of ketone bodies,pyrimidine metabolism,β-alanine metabolism,and retinal metabolism.展开更多
Objective:To investigate the effect of epigallocatechin-3-gallate(EGCG)on endothelial dysfunction in spontaneously hypertensive rats(SHR).Methods:Wistar-Kyoto(WKY)rats and SHR were divided into four groups;WKY control...Objective:To investigate the effect of epigallocatechin-3-gallate(EGCG)on endothelial dysfunction in spontaneously hypertensive rats(SHR).Methods:Wistar-Kyoto(WKY)rats and SHR were divided into four groups;WKY control,SHR control and SHR treated with EGCG(50 mg/kg/day)or losartan(10 mg/kg/day).The treatment was given daily for 4 weeks by oral gavage and the blood pressure was monitored by tail-cuff method every 3 days.Acetylcholineinduced endothelium-dependent relaxations were assessed in isolated phenylephrine-precontracted aortic rings at the end of treatment.The vascular levels of reactive oxygen species,nitric oxide,tetrahydrobiopterin,and cyclic guanosine monophosphate were also measured.Moreover,the expression of angiotensinⅡtype 1(AT_(1))receptor protein was determined.Results:The systolic blood pressure was significantly decreased in SHR treated with EGCG.The impaired endothelium-dependent relaxation was significantly improved in aortic ring isolated from the EGCG-treated SHR group.EGCG also significantly increased the levels of nitric oxide,tetrahydrobiopterin,and cyclic guanosine monophosphate,while decreasing the level of reactive oxygen species and the protein expression of AT_(1)receptor in SHR.Conclusions:EGCG attenuates endothelial dysfunction in SHR by decreasing oxidative stress and increasing vascular nitric oxide bioavailability,which may be modulated partly by inhibition of vascular AT_(1)receptors.An increase in endothelium-dependent relaxation may contribute to a decrease in blood pressure in hypertensive animals.展开更多
Objective:To investigate a hippocampal anti-hypertensive mechanism induced by twirling reinforcingreducing manipulation(TRRM)using proteomics in rats.Methods:Forty-two male spontaneously hypertensive rats were randoml...Objective:To investigate a hippocampal anti-hypertensive mechanism induced by twirling reinforcingreducing manipulation(TRRM)using proteomics in rats.Methods:Forty-two male spontaneously hypertensive rats were randomly divided into 3 groups,and 14 Wistar-Kyoto rats were served as control group.In the twirling reinforcing(TRF)group,needles were directly inserted into the Taichong(LR 3)point,then thumbs were moved heavily forward and lightly backward for 3 min,while needles remained inserted for 17 min.In the twirling reduction(TRD)group,the same treatment was applied as in the TRF group except that the thumb moved lightly forward and heavily backward.In the model and control groups,only the corresponding grasping and fixation were applied.All interventions were conducted for 14 days.The blood pressure(BP)of all rats was measured one day before intervention and every other day after.Then hematoxylin-eosin(H&E)staining,label-free and parallel reaction monitoring proteomic techniques were used to assess hippocampal samples from each group.Results:Systolic BPs showed a significant decrease in the TRF and TRD groups compared with the model group(P<.01).In the model group,H&E staining showed obvious pathological changes in the hippocampus,while in the TRF and TRD groups,the hippocampal morphology was only slightly altered.Labelfree proteomic analysis revealed 1163 differential protein expressions between groups.Gene Ontology enrichment analysis confirmed that the differentially expressed proteins were enriched in different biological processes,cellular components,and molecular functions.Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that TRRM proteins were expressed in the serotonergic synapse pathway,renin-angiotensin system,the mitogen-activated protein kinase signaling pathway,and the peroxisome pathway,which were all also related to BP regulation.Conclusion:TRRM can significantly lower the BP of SHRs.The mode of action may be through the activation of various protein pathways in the hippocampus that are related to BP regulation.展开更多
The abnormal growth of epithelium-like cells has been noticed in spontaneously hypertensive rats(SHRs)with hypertensive nephropathy.However,the characteristics of abnormal epithelium-like cells and their pathogenesis ...The abnormal growth of epithelium-like cells has been noticed in spontaneously hypertensive rats(SHRs)with hypertensive nephropathy.However,the characteristics of abnormal epithelium-like cells and their pathogenesis in hypertensive nephropathy are not fully understood.In the present study,we investigated the correlation of epithelium-like cells with glomerular injury,and the effects of early drug intervention with telmisartan,an anti-hypertensive drug,on the growth of epithelium-like cells.The results showed that the epithelium-like cells were obviously observed lining along the luminal surface of Bowman’s capsule in glomeruli,significantly resulting in the atrophy of the glomerular tuft.Some of the epithelium-like cells strongly expressed proliferating cell nuclear antigen(PCNA)and vimentin,indicating active cellular proliferation.The incidence of epithelium-like cells varied from 13.6%to 54.4%of glomeruli in 48-week-old SHRs,and from 5.1%to 18.0%of glomeruli in age-matched Wistar-Kyoto(WKY)rats(P<0.01).The linear regression analysis further confirmed an obvious correlation between the incidence of epithelium-like cells and the glomerular injury.Moreover,early intervention with telmisartan could dramatically attenuate the progression of epithelium-like cells growth.However,no significant effect of telmisartan on the established epithelium-like cells was observed.Taken together,we demonstrated the involvement of abnormal epithelium-like cells growth in glomerular injury during hypertensive nephropathy in SHRs,and firstly showed the positive effects of the anti-hypertensive drug on the progression of epithelium-like cells growth.展开更多
OBJECTIVE To investigate the inhibitory effect and mechanism of sodium ferulate(SF)on myocardial hypertrophy in spontaneously hypertensive(SHR).METHODS Forty 14-week-old SHR male rats were randomly divided into model ...OBJECTIVE To investigate the inhibitory effect and mechanism of sodium ferulate(SF)on myocardial hypertrophy in spontaneously hypertensive(SHR).METHODS Forty 14-week-old SHR male rats were randomly divided into model group(SHR,receive distilled water)and SF treatment groups(SF 20,40 and 80 mg·kg^-1 per day,respectively).Age-matched male Wistar-Kyoto(WKY)rats gavaged with distilled water served as controls.After 12 weeks of treatment,the effects of SF on cardiac hypertrophy were evaluated using echocardiographic measurement,pathological analysis and the expression of atrial natriuretic peptide(ANP),myosin heavy chainβ(β-MHC)-a gene related to myocardial hypertrophy.In order to explore the mechanism of SF on myocardial hypertrophy,the calcium-sensing receptor(CaSR),calcineurin(CaN),nuclear factor of activated T cell 3(NFAT3),phosphorylation NFAT3(p-NFAT3),zinc finger transcription factor(GATA4),phosphorylation GATA4(p-GATA4),protein kinase Cβ(PKC-β),Raf-1,extracellular regulated protein kinase 1/2(ERK 1/2),phosphorylation ERK1/2(p-ERK 1/2)and mitogen-activated protein kinase phosphatase-1(MKP-1)were detected.RESULTS The myocardial hypertrophy parameters,myocardial cell cross section area,left ventricular wall thickness and expression of ANP and β-MHC,CaSR,CaN,NFAT3,p-GATA4,PKC-β,Raf-1,and p-ERK 1/2 were significantly increased,while the left ventricular cavity was significantly smaller,expression of p-NFAT3 and MKP-1 were significantly decreased,meanwhile,the ultra⁃structure of cardiomyocytes was significantly damaged in 26-week-old SHR rats.Notably,SF significantly ameliorated myocardial hyper⁃trophy in 26-week-old SHR rats;suppressed the overexpression of ANP,β-MHC,CaSR,CaN,NFAT3,p-GATA4,PKC-β,Raf-1,and p-ERK 1/2 and increased the expression of p-NFAT3 and MKP-1.CONCLUSION SF can inhibit cardiac hypertrophy in SHR rats,and the mechanism may be related to the inhibition of CaSR mediated signaling pathway.展开更多
Objective: Hypertension is a low-grade infammation state of the disease and was easily complicated by kidneys’ infammatory response. Mangiferin(MGF), a pharmacologically active compound in various plants including Ma...Objective: Hypertension is a low-grade infammation state of the disease and was easily complicated by kidneys’ infammatory response. Mangiferin(MGF), a pharmacologically active compound in various plants including Mangifera indica, has a strong anti-infammatory activity. However, the effects of MGF on renal infammatory injury in spontaneously hypertensive rats(SHRs) remain unclear. The purpose of this study was to investigate the protective effects and mechanisms of MGF on renal infammatory injury in SHRs.Methods: MGF was used in SHRs at the doses of 10, 20, 40 mg/kg/d for 8 weeks consecutively. The blood and urine were collected for assessment of renal function. Renal tissues were collected for histological,immunohistochemistry, ELISA, Western blot and real time reverse transcription PCR(RT-PCR) analysis.Results: The results showed that the levels of interleukin 6(IL-6), tumor necrosis factor-a(TNF-a), monocyte chemoattractant protein-1(MCP-1) and recombinant chemokine C-C-Motif receptor 2(CCR2) were increased in SHRs, meanwhile, the level of IL-10 was decreased in SHR. Treatment of MGF inhibited the expression of IL-6, TNF-a, MCP-1 and CCR2, and promoted the expression of IL-10. Furthermore, the content of blood urea nitrogen(BUN) and serum uric acid(SUA) was significantly increased in the model group, and treatment of MGF had no obvious effects on these parameters at all dose levels.Conclusion: Our study proved that the kidneys of SHRs had significant infammatory injury, and MGF had the protective effects on renal infammatory injury in SHRs;The protective mechanism may be mediated partly by the MCP-1/CCR2 signaling pathway. Thus, it is a potential new drug for the treatment of hypertension.展开更多
Objective: To investigate the bioactive components of Sangqi Qingxuan formula(SQQX), predict the pharmacological targets, and explore the mechanism of hypertensive vascular remodeling(HVR).Methods: Network pharmacolog...Objective: To investigate the bioactive components of Sangqi Qingxuan formula(SQQX), predict the pharmacological targets, and explore the mechanism of hypertensive vascular remodeling(HVR).Methods: Network pharmacology was adopted to predict how SQQX acts in HVR. The effectiveness was assessed by blood pressure measurements and pathological morphology observation based on a spontaneously hypertensive rat model, while the mechanism of SQQX on HVR was validated by immunohistochemistry(IHC) and western blot(WB) according to the results of network pharmacology.Results: There were 130 bioactive components of SQQX and 231 drug targets predicted by the Traditional Chinese Medicine Systems Pharmacology Database. Subsequently, 181 common targets were identified for SQQX against HVR, with TP53, MAPK1, and AKT1 as the core targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses was employed to identify the top 20 enriched functions and the top 20 pathways(P <.01). Finally, the key role of the ERK/MAPK signaling pathway in HVR was determined. The in vivo results suggested that SQQX reduced systolic blood pressure and increased the ratio of thoracic aortic wall thickness to lumen diameter. Additionally, compared with the model group, SQQX increased the expression of smooth muscle 22 alpha(IHC: P <.001;WB:P <.05) and decreased the expression of osteopontin(IHC: P <.001;WB: P <.05), ERK1/2(IHC: P <.001;WB: ERK1 & ERK2, all P <.05), p-ERK1/2(IHC: P <.001;WB: ERK1 & ERK2, all P <.05), and the ratio of pERK1/2 to ERK1/2 protein(IHC: P <.001).Conclusions: SQQX, which has multiple bioactive ingredients and potential targets, is an effective treatment for HVR. The mechanism of antihypertensive and vascular protection may be related to the inhibition of phenotypic transformation of vascular smooth muscle cells and the ERK/MAPK signaling pathway.展开更多
[Objectives] To study the effects of Mangiferin( MGF) on TNF-α,iNOS,ICAM-1 and its mRNA expression in the heart,brain and kidneys of spontaneously hypertensive rats( SHR),and reveal the mechanism of its anti-inflamma...[Objectives] To study the effects of Mangiferin( MGF) on TNF-α,iNOS,ICAM-1 and its mRNA expression in the heart,brain and kidneys of spontaneously hypertensive rats( SHR),and reveal the mechanism of its anti-inflammatory injury in hypertension target organs.[Methods]SHRs were randomly divided into 5 groups: the model group,the high-dose,medium-dose,low-dose MGF groups and the Benazepril group,with 8 rats in each group,WKY rats were used for the normal control group. Besides,on-invasive blood pressure( BP) instruments were used to measure systolic blood pressure in the rats' tail artery,western blot was used to analyze the expression of TNF-α,iNOS,ICAM-1 and reverse transcription-polymerase chain reaction( RT-PCR) was used to analyze the expression of TNF-α,iNOS,ICAM-1 mRNA.[Results]Compared with the normal control group,the model group's BP level was significantly increased( P <0. 01)),but the MGF had no significant lowering BP effect( P > 0. 05); compared with the normal control group,the expression of TNF-α,iNOS,ICAM-1 and its' mRNA in the model group was significantly increased( P < 0. 05 or P < 0. 01),and MGF could reduce the level of expression of these inflammatory cytokines( P < 0. 05 or P < 0. 01); between the Benazepril group and high-dose,medium-dose,low-dose MGF groups,most of the indicators had no significant difference( P > 0. 05). [Conclusions]MGF had no significant lowering BP effect,SHR showed inflammatory injury in the heart,brain and kidneys,MGF showed improvement on the inflammatory injury,and the anti-inflammation mechanism may be associated with lowering TNF-α,i NOS and ICAM-1 and its mRNA expression.展开更多
Objective: To investigate the effect of electroacupuncture(EA) at Neiguan(PC 6) on myocardial fibrosis in spontaneously hypertensive rats(SHRs), and to explore the contribution of interleukin-1β(IL-1β),insulin-like ...Objective: To investigate the effect of electroacupuncture(EA) at Neiguan(PC 6) on myocardial fibrosis in spontaneously hypertensive rats(SHRs), and to explore the contribution of interleukin-1β(IL-1β),insulin-like growth factor 1(IGF-1), and transforming growth factor β1(TGF-β1) to the effects. Methods:Nine 12-weeks-old Wistar Kyoto(WKY) male rats were employed as the normal group. Twenty-seven SHRs were equally randomized into SHR, SHR+EA, and SHR + sham groups. EA was applied at bilateral PC 6once a day 30 min per day in 8 consecutive weeks. After 8-weeks EA treatment at PC 6, histopathologic changes of collagen type Ⅰ(Col Ⅰ), collagen type Ⅲ(Col Ⅲ) and the levels of IGF-1, 1L-1β, TGF-β1,matrix metalloproteinase(MMP)-2 and MMP-9 were examined in myocardial tissure respectively. Results:After 8-weeks EA treatment at PC 6, the enhanced myocardial fibrosis in SHRs were characterized by the increased mean fluorescence intensity of Col Ⅰ and Col Ⅲ in myocardium tissue(P<0.01). All these abnormal alterations above in SHR + EA group was significantly lower compared with the SHR group(P<0.01). Meanwhile,the increased levels of IL-1β, IGF-1, TGF-β1 in serum or myocardial tissue of SHRs, diminished MMP 9mRNA expression in SHRs were also markedly inhibited after 8 weeks of EA treatment(P<0.05 or P<0.01).Furthermore, the contents of IL-1β, IGF-1, TGF-β1 in myocardial tissue were positively correlated with the systolic blood pressure and hydroxyproline respectively(P<0.01). Conclusion: EA at bilateral PC 6 could ameliorate cardiac fibrosis in SHRs, which might be mediated by regulation of 1L-1β/IGF-1-TGF-β1-MMP9 pathway.展开更多
基金Supported by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo,No.FAPESP,2011/13974-8Coordenacao de Aperfeicoamento de Pessoal de Nível Superior(CAPES)
文摘AIM To study hepatic vasoconstriction and glucose release induced by angiotensin(Ang)Ⅱ or Epi in rats with pharmacological hypertension and spontaneously hypertensive rat(SHR).METHODS Isolated liver perfusion was performed following portal vein and vena cava cannulation; AngⅡ or epinephrine(Epi) was injected in bolus and portal pressure monitored; glucose release was measured in perfusate aliquots. RESULTS The portal hypertensive response(PHR) and the glucose release induced by AngⅡ of L-NAME were similar to normal rats(WIS). On the other hand, the PHR inducedby Epi in L-NAME was higher whereas the glucose release was lower compared to WIS. Despite the similar glycogen content, glucose release induced by AngⅡ was lower in SHR compared to Wistar-Kyoto rats although both PHR and glucose release induced by Epi in were similar. CONCLUSION AngⅡ and Epi responses are altered in different ways in these hypertension models. Our results suggest that inhibition of NO production seems to be involved in the hepatic effects induced by Epi but not by AngⅡ; the diminished glucose release induced by AngⅡ in SHR is not related to glycogen content.
基金supported by the National Natural Science Foundation of China(No.31901635)。
文摘The angiotensin-converting enzyme(ACE)inhibitory peptide NCW derived from Mizuhopecten yessoensis has been demonstrated to have significant in vivo anti-hypertensive effects,however,its anti-hypertensive mechanism is still not fully clarified.This study established a UPLC-Q-TRAP-MS/MS-based widely targeted kidney metabolomics approach to explore the changes of kidney metabolic profiles and to clarify the antihypertensive mechanism of peptide NCW in spontaneously hypertensive rats(SHRs).Multivariate statistical analysis indicated that the kidney metabolic profiles were clearly separated between the SHR-NCW and SHRUntreated groups.A total of 85 metabolites were differentially regulated,and 16 metabolites were identified as potential kidney biomarkers,e.g.,3-hydroxybutyrate,malonic acid,deoxycytidine,and L-aspartic acid.The peptide NCW might regulate kidney metabolic disorder of SHRs to alleviate hypertension by suppressing inflammation and improving nitric oxide production under the regulation of linoleic acid metabolism,folate related pathways,synthesis and degradation of ketone bodies,pyrimidine metabolism,β-alanine metabolism,and retinal metabolism.
基金funded by the Universiti Tunku Abdul Rahman Research fund(IPSR/RMC/UTARRF/2019-C2/L08)。
文摘Objective:To investigate the effect of epigallocatechin-3-gallate(EGCG)on endothelial dysfunction in spontaneously hypertensive rats(SHR).Methods:Wistar-Kyoto(WKY)rats and SHR were divided into four groups;WKY control,SHR control and SHR treated with EGCG(50 mg/kg/day)or losartan(10 mg/kg/day).The treatment was given daily for 4 weeks by oral gavage and the blood pressure was monitored by tail-cuff method every 3 days.Acetylcholineinduced endothelium-dependent relaxations were assessed in isolated phenylephrine-precontracted aortic rings at the end of treatment.The vascular levels of reactive oxygen species,nitric oxide,tetrahydrobiopterin,and cyclic guanosine monophosphate were also measured.Moreover,the expression of angiotensinⅡtype 1(AT_(1))receptor protein was determined.Results:The systolic blood pressure was significantly decreased in SHR treated with EGCG.The impaired endothelium-dependent relaxation was significantly improved in aortic ring isolated from the EGCG-treated SHR group.EGCG also significantly increased the levels of nitric oxide,tetrahydrobiopterin,and cyclic guanosine monophosphate,while decreasing the level of reactive oxygen species and the protein expression of AT_(1)receptor in SHR.Conclusions:EGCG attenuates endothelial dysfunction in SHR by decreasing oxidative stress and increasing vascular nitric oxide bioavailability,which may be modulated partly by inhibition of vascular AT_(1)receptors.An increase in endothelium-dependent relaxation may contribute to a decrease in blood pressure in hypertensive animals.
基金supported by the National Natural Science Foundation of China(82074553)the Qilu Traditional Chinese Medicine Oriented Specialty Cluster,Rehabilitation Group 2.
文摘Objective:To investigate a hippocampal anti-hypertensive mechanism induced by twirling reinforcingreducing manipulation(TRRM)using proteomics in rats.Methods:Forty-two male spontaneously hypertensive rats were randomly divided into 3 groups,and 14 Wistar-Kyoto rats were served as control group.In the twirling reinforcing(TRF)group,needles were directly inserted into the Taichong(LR 3)point,then thumbs were moved heavily forward and lightly backward for 3 min,while needles remained inserted for 17 min.In the twirling reduction(TRD)group,the same treatment was applied as in the TRF group except that the thumb moved lightly forward and heavily backward.In the model and control groups,only the corresponding grasping and fixation were applied.All interventions were conducted for 14 days.The blood pressure(BP)of all rats was measured one day before intervention and every other day after.Then hematoxylin-eosin(H&E)staining,label-free and parallel reaction monitoring proteomic techniques were used to assess hippocampal samples from each group.Results:Systolic BPs showed a significant decrease in the TRF and TRD groups compared with the model group(P<.01).In the model group,H&E staining showed obvious pathological changes in the hippocampus,while in the TRF and TRD groups,the hippocampal morphology was only slightly altered.Labelfree proteomic analysis revealed 1163 differential protein expressions between groups.Gene Ontology enrichment analysis confirmed that the differentially expressed proteins were enriched in different biological processes,cellular components,and molecular functions.Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that TRRM proteins were expressed in the serotonergic synapse pathway,renin-angiotensin system,the mitogen-activated protein kinase signaling pathway,and the peroxisome pathway,which were all also related to BP regulation.Conclusion:TRRM can significantly lower the BP of SHRs.The mode of action may be through the activation of various protein pathways in the hippocampus that are related to BP regulation.
基金the General Financial Grant from the China Postdoctoral Science Foundation(No.2014M560722)the Natural Science Foundation of Sichuan University of Science and Engineering(No.2015RC30)the Science and Technology Support Program of Sichuan Province of China(No.2017RZ0083).
文摘The abnormal growth of epithelium-like cells has been noticed in spontaneously hypertensive rats(SHRs)with hypertensive nephropathy.However,the characteristics of abnormal epithelium-like cells and their pathogenesis in hypertensive nephropathy are not fully understood.In the present study,we investigated the correlation of epithelium-like cells with glomerular injury,and the effects of early drug intervention with telmisartan,an anti-hypertensive drug,on the growth of epithelium-like cells.The results showed that the epithelium-like cells were obviously observed lining along the luminal surface of Bowman’s capsule in glomeruli,significantly resulting in the atrophy of the glomerular tuft.Some of the epithelium-like cells strongly expressed proliferating cell nuclear antigen(PCNA)and vimentin,indicating active cellular proliferation.The incidence of epithelium-like cells varied from 13.6%to 54.4%of glomeruli in 48-week-old SHRs,and from 5.1%to 18.0%of glomeruli in age-matched Wistar-Kyoto(WKY)rats(P<0.01).The linear regression analysis further confirmed an obvious correlation between the incidence of epithelium-like cells and the glomerular injury.Moreover,early intervention with telmisartan could dramatically attenuate the progression of epithelium-like cells growth.However,no significant effect of telmisartan on the established epithelium-like cells was observed.Taken together,we demonstrated the involvement of abnormal epithelium-like cells growth in glomerular injury during hypertensive nephropathy in SHRs,and firstly showed the positive effects of the anti-hypertensive drug on the progression of epithelium-like cells growth.
基金National Natural Science Foundation of China(81860732)Scientific and Technological Projects for Social Development in Guizhou Province of China([2011]3036)the State Key Laboratory of Cardiovascular Disease(2017kf-03)
文摘OBJECTIVE To investigate the inhibitory effect and mechanism of sodium ferulate(SF)on myocardial hypertrophy in spontaneously hypertensive(SHR).METHODS Forty 14-week-old SHR male rats were randomly divided into model group(SHR,receive distilled water)and SF treatment groups(SF 20,40 and 80 mg·kg^-1 per day,respectively).Age-matched male Wistar-Kyoto(WKY)rats gavaged with distilled water served as controls.After 12 weeks of treatment,the effects of SF on cardiac hypertrophy were evaluated using echocardiographic measurement,pathological analysis and the expression of atrial natriuretic peptide(ANP),myosin heavy chainβ(β-MHC)-a gene related to myocardial hypertrophy.In order to explore the mechanism of SF on myocardial hypertrophy,the calcium-sensing receptor(CaSR),calcineurin(CaN),nuclear factor of activated T cell 3(NFAT3),phosphorylation NFAT3(p-NFAT3),zinc finger transcription factor(GATA4),phosphorylation GATA4(p-GATA4),protein kinase Cβ(PKC-β),Raf-1,extracellular regulated protein kinase 1/2(ERK 1/2),phosphorylation ERK1/2(p-ERK 1/2)and mitogen-activated protein kinase phosphatase-1(MKP-1)were detected.RESULTS The myocardial hypertrophy parameters,myocardial cell cross section area,left ventricular wall thickness and expression of ANP and β-MHC,CaSR,CaN,NFAT3,p-GATA4,PKC-β,Raf-1,and p-ERK 1/2 were significantly increased,while the left ventricular cavity was significantly smaller,expression of p-NFAT3 and MKP-1 were significantly decreased,meanwhile,the ultra⁃structure of cardiomyocytes was significantly damaged in 26-week-old SHR rats.Notably,SF significantly ameliorated myocardial hyper⁃trophy in 26-week-old SHR rats;suppressed the overexpression of ANP,β-MHC,CaSR,CaN,NFAT3,p-GATA4,PKC-β,Raf-1,and p-ERK 1/2 and increased the expression of p-NFAT3 and MKP-1.CONCLUSION SF can inhibit cardiac hypertrophy in SHR rats,and the mechanism may be related to the inhibition of CaSR mediated signaling pathway.
基金supported by Natural Science Foundation of Guangxi Province (No. 2013GXNSFAA019114)Guangxi Key Laboratory of Efficacy Study on Chinese Materia Medica Project (No. 12-071-08)。
文摘Objective: Hypertension is a low-grade infammation state of the disease and was easily complicated by kidneys’ infammatory response. Mangiferin(MGF), a pharmacologically active compound in various plants including Mangifera indica, has a strong anti-infammatory activity. However, the effects of MGF on renal infammatory injury in spontaneously hypertensive rats(SHRs) remain unclear. The purpose of this study was to investigate the protective effects and mechanisms of MGF on renal infammatory injury in SHRs.Methods: MGF was used in SHRs at the doses of 10, 20, 40 mg/kg/d for 8 weeks consecutively. The blood and urine were collected for assessment of renal function. Renal tissues were collected for histological,immunohistochemistry, ELISA, Western blot and real time reverse transcription PCR(RT-PCR) analysis.Results: The results showed that the levels of interleukin 6(IL-6), tumor necrosis factor-a(TNF-a), monocyte chemoattractant protein-1(MCP-1) and recombinant chemokine C-C-Motif receptor 2(CCR2) were increased in SHRs, meanwhile, the level of IL-10 was decreased in SHR. Treatment of MGF inhibited the expression of IL-6, TNF-a, MCP-1 and CCR2, and promoted the expression of IL-10. Furthermore, the content of blood urea nitrogen(BUN) and serum uric acid(SUA) was significantly increased in the model group, and treatment of MGF had no obvious effects on these parameters at all dose levels.Conclusion: Our study proved that the kidneys of SHRs had significant infammatory injury, and MGF had the protective effects on renal infammatory injury in SHRs;The protective mechanism may be mediated partly by the MCP-1/CCR2 signaling pathway. Thus, it is a potential new drug for the treatment of hypertension.
基金supported by the National Natural Science Foundation of China (81774105)。
文摘Objective: To investigate the bioactive components of Sangqi Qingxuan formula(SQQX), predict the pharmacological targets, and explore the mechanism of hypertensive vascular remodeling(HVR).Methods: Network pharmacology was adopted to predict how SQQX acts in HVR. The effectiveness was assessed by blood pressure measurements and pathological morphology observation based on a spontaneously hypertensive rat model, while the mechanism of SQQX on HVR was validated by immunohistochemistry(IHC) and western blot(WB) according to the results of network pharmacology.Results: There were 130 bioactive components of SQQX and 231 drug targets predicted by the Traditional Chinese Medicine Systems Pharmacology Database. Subsequently, 181 common targets were identified for SQQX against HVR, with TP53, MAPK1, and AKT1 as the core targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses was employed to identify the top 20 enriched functions and the top 20 pathways(P <.01). Finally, the key role of the ERK/MAPK signaling pathway in HVR was determined. The in vivo results suggested that SQQX reduced systolic blood pressure and increased the ratio of thoracic aortic wall thickness to lumen diameter. Additionally, compared with the model group, SQQX increased the expression of smooth muscle 22 alpha(IHC: P <.001;WB:P <.05) and decreased the expression of osteopontin(IHC: P <.001;WB: P <.05), ERK1/2(IHC: P <.001;WB: ERK1 & ERK2, all P <.05), p-ERK1/2(IHC: P <.001;WB: ERK1 & ERK2, all P <.05), and the ratio of pERK1/2 to ERK1/2 protein(IHC: P <.001).Conclusions: SQQX, which has multiple bioactive ingredients and potential targets, is an effective treatment for HVR. The mechanism of antihypertensive and vascular protection may be related to the inhibition of phenotypic transformation of vascular smooth muscle cells and the ERK/MAPK signaling pathway.
基金Supported by the Guangxi Science and Technology Infrastructure Construction Project of China(09-007-06)
文摘[Objectives] To study the effects of Mangiferin( MGF) on TNF-α,iNOS,ICAM-1 and its mRNA expression in the heart,brain and kidneys of spontaneously hypertensive rats( SHR),and reveal the mechanism of its anti-inflammatory injury in hypertension target organs.[Methods]SHRs were randomly divided into 5 groups: the model group,the high-dose,medium-dose,low-dose MGF groups and the Benazepril group,with 8 rats in each group,WKY rats were used for the normal control group. Besides,on-invasive blood pressure( BP) instruments were used to measure systolic blood pressure in the rats' tail artery,western blot was used to analyze the expression of TNF-α,iNOS,ICAM-1 and reverse transcription-polymerase chain reaction( RT-PCR) was used to analyze the expression of TNF-α,iNOS,ICAM-1 mRNA.[Results]Compared with the normal control group,the model group's BP level was significantly increased( P <0. 01)),but the MGF had no significant lowering BP effect( P > 0. 05); compared with the normal control group,the expression of TNF-α,iNOS,ICAM-1 and its' mRNA in the model group was significantly increased( P < 0. 05 or P < 0. 01),and MGF could reduce the level of expression of these inflammatory cytokines( P < 0. 05 or P < 0. 01); between the Benazepril group and high-dose,medium-dose,low-dose MGF groups,most of the indicators had no significant difference( P > 0. 05). [Conclusions]MGF had no significant lowering BP effect,SHR showed inflammatory injury in the heart,brain and kidneys,MGF showed improvement on the inflammatory injury,and the anti-inflammation mechanism may be associated with lowering TNF-α,i NOS and ICAM-1 and its mRNA expression.
基金Supported by the National Natural Science Foundation of China(No.81804211,No.81774439)China Academy of Chinese Medical Sciences Foundation(No.ZZ13-YQ-065)。
文摘Objective: To investigate the effect of electroacupuncture(EA) at Neiguan(PC 6) on myocardial fibrosis in spontaneously hypertensive rats(SHRs), and to explore the contribution of interleukin-1β(IL-1β),insulin-like growth factor 1(IGF-1), and transforming growth factor β1(TGF-β1) to the effects. Methods:Nine 12-weeks-old Wistar Kyoto(WKY) male rats were employed as the normal group. Twenty-seven SHRs were equally randomized into SHR, SHR+EA, and SHR + sham groups. EA was applied at bilateral PC 6once a day 30 min per day in 8 consecutive weeks. After 8-weeks EA treatment at PC 6, histopathologic changes of collagen type Ⅰ(Col Ⅰ), collagen type Ⅲ(Col Ⅲ) and the levels of IGF-1, 1L-1β, TGF-β1,matrix metalloproteinase(MMP)-2 and MMP-9 were examined in myocardial tissure respectively. Results:After 8-weeks EA treatment at PC 6, the enhanced myocardial fibrosis in SHRs were characterized by the increased mean fluorescence intensity of Col Ⅰ and Col Ⅲ in myocardium tissue(P<0.01). All these abnormal alterations above in SHR + EA group was significantly lower compared with the SHR group(P<0.01). Meanwhile,the increased levels of IL-1β, IGF-1, TGF-β1 in serum or myocardial tissue of SHRs, diminished MMP 9mRNA expression in SHRs were also markedly inhibited after 8 weeks of EA treatment(P<0.05 or P<0.01).Furthermore, the contents of IL-1β, IGF-1, TGF-β1 in myocardial tissue were positively correlated with the systolic blood pressure and hydroxyproline respectively(P<0.01). Conclusion: EA at bilateral PC 6 could ameliorate cardiac fibrosis in SHRs, which might be mediated by regulation of 1L-1β/IGF-1-TGF-β1-MMP9 pathway.
