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ObjectiveTo explore the underlying mechanism of modified Zhenwutang in delaying renal interstitial fibrosis in chronic renal failure （CRF） by observing the effects of modified Zhenwutang on the expression of angiotensin Ⅱ （Ang Ⅱ）， angiotensin Ⅱ type 1 receptor （AT1R）， nicotinamide adenine dinucleotide phosphate （NADPH） oxidase 4 （NOX4）， transforming growth factor-β1 （TGF-β1）， type I collagen （COL1A1）， and type Ⅲ collagen （COL3A1） in the serum and renal tissues of adenine-induced CRF rats. MethodFifty male SPF-grade SD rats were randomly divided into a normal group （n=10） and an experimental group （n=40） using a random number table. After one week of adaptive feeding， the experimental CRF model was established in rats by administering adenine at 150 mg·kg-1·d-1 orally. Three rats from each group were randomly selected to evaluate the model induction. After successful modeling， rats in the experimental group were randomly divided into a model group， low-， medium， and high-dose modified Zhenwutang groups， and a benazepril hydrochloride group， with six rats in each group. The rats were orally administered the corresponding drugs once daily for four weeks. At the end of the first week， 13th week， and 17th week of the experiment， 24 hour urinary protein quantification （24 h-UTP） was measured. At the end of the 17th week， the rats were euthanized， and blood samples were collected from the abdominal aorta for the measurement of total protein （TP）， albumin （ALB）， creatinine （Cr）， and blood urea nitrogen （BUN） in the serum. Enzyme-linked immunosorbent assay （ELISA） was used to measure the expression levels of serum Ang Ⅱ. Hematoxylin-eosin （HE） staining and Masson's trichrome staining were performed to observe the pathological changes in renal tissues. Immunohistochemistry （IHC） was performed to observe the expression of AT1R， NOX4， TGF-β1， COL1A1， and COL3A1. Real-time fluorescence-based quantitative polymerase chain reaction （Real-time PCR） was used to observe the mRNA expression levels of AT1R， NOX4， and TGF-β1. Western blot was conducted to measure the protein expression levels of AT1R， NOX4， and TGF-β1. Result① Compared with the normal group， the model group showed a significant increase in 24 h-UTP （P<0.01）. The levels of Cr and BUN in the model group were significantly higher （P<0.01）， while the levels of TP and ALB were significantly lower （P<0.01）. The serum Ang Ⅱ level in the model group was significantly elevated （P<0.01）. The model group exhibited widening of the renal glomerular mesangial space， necrotic glomeruli， increased interstitial width with extensive inflammatory cell infiltration， brownish precipitates blocking the renal tubular lumens， irregular renal tubules， and significant deposition of collagen fibers in the renal interstitium. Additionally， the collagen fibers around the renal vessels， outside the parietal layer of the renal sacs， glomerular basement membrane， and tubular basement membrane increased significantly. The expression of AT1R and NOX4 in the glomeruli and renal tubules of the model group was significantly enhanced， and TGF-β1 expression also significantly increased in the renal tubules. The expression of COL1A1 and COL3A1 in the renal interstitium significantly increased. The mRNA expression of AT1R and TGF-β1 in the model group significantly increased （P<0.01）， while NOX4 mRNA expression significantly decreased （P<0.01）. The protein expression of AT1R， NOX4， and TGF-β1 was significantly enhanced （P<0.01）. ② Compared with the model group， modified Zhenwutang significantly reduced 24h-UTP （P<0.01）， decreased levels of Cr and BUN （P<0.01）， increased levels of TP and ALB （P<0.01）， reduced serum Ang Ⅱ level （P<0.01）， alleviated renal pathological damage， reduced expression of AT1R， NOX4， TGF-β1， COL1A1， and COL3A1 in the glomeruli， renal tubules， and renal interstitium， reduced mRNA expression of AT1R and TGF-β1 （P<0.01）， increased NOX4 mRNA expression （P<0.01）， and weakened protein expression of AT1R， NOX4， and TGF-β1 （P<0.01）. The modified Zhenwutang groups showed a significant dose-effect trend. ConclusionModified Zhenwutang may delay renal interstitial fibrosis in CRF rats by reducing the expression of Ang Ⅱ， AT1R， NOX4， and TGF-β1 in the serum and renal tissues， thereby alleviating renal pathological damage， reducing proteinuria， protecting renal function， and delaying the progression of CRF. The modified Zhenwutang group exhibited a dose-effect trend.
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Objective：To assess the risk for hyperkalemia caused by treatment with angiotensin Ⅱ Type 1 receptor blockers （ARB） in clinical practice with Japanese medical database.Design：A cohort study in patients treated with ARB alone and those treated with calcium channel blockers （CCB） alone as control.Methods：The Diagnosis Procedure Combination （DPC） database provided by Medical Data Vision Co., Ltd. was used to identify patients who received a diagnosis of hypertension (ICD-10 codes, I10 to I15) and were treated with ARB or CCB from April 2008 to June 2017. A logistic regression model was applied to estimate adjusted odds ratios （OR） and their 95％ confidence intervals （CI） in these patients. The outcome in the logistic model was hyperkalemia （serum potassium≧5.5 mEq/L） and the covariates were sex, age, renal insufficiency, hepatic insufficiency, and baseline serum potassium levels. And, subgroup analysis was also performed in patients with and without renal insufficiency.Results：The incidence of hyperkalemia （per 1000 person-years） with ARB was 39.4 and that with CCB was 32.6. And, median periods from the index date to the date of occurrence of hyperkalemia for both exposure and control groups were 36 days （Min-Max：12-85） and 51.5 days（Min-Max：8-88）respectively. However, treatment with ARB was not associated with occurrence of hyperkalemia （OR 1.26, 95％CI： 0.58-2.75). The risk for hyperkalemia among those with renal insufficiency was higher （OR 3.31, 95％CI： 1.39-7.88）and as baseline serum potassium increased, the risk increased as well （OR 9.20, 95％CI： 3.52-24.10). And, the subgroup analysis also showed that rare occurrence of hyperkalemia by ARB and elevation risk for hyperkalemia by baseline serum potassium.Conclusion：The clinical data showed rare occurrence of hyperkalemia caused by ARB, indicating that renal insufficiency and baseline serum potassium levels affected the onset of the disease in clinical practice. Previous studies also reported the effects of renal insufficiency and other factors on the onset of hyperkalemia. ARB should be prescribed carefully in patients with these factors, as is conventionally done.
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AIM:To investigate the mechanism of angiotensinⅡ(AngⅡ)/angiotensinⅡ type 1 receptor (AT1R)pathway activating protein phosphatase 2A(PP2A)which leads to down-regulation endothelial nitric oxide syn-thase(eNOS)phosphorylation level in mesenteric arteries of rats.METHODS: METHODS: The mesenteric arteries of adult male SD rats(weighing 160~180 g;n=90)were isolated under aseptic conditions.Firstly,to determine the effect of angiotensinⅡdown-regulated eNOS(Ser1177)phosphorylation level,the mesenteric arteries were randomly divided into normal control(control)group and AngⅡgroup.The mesenteric arteries in AngⅡgroup were incubated with AngⅡat 1×10 -7mol/L,1×10 -6mol/L and 1×10 -5mol/L for 6 h,12 h and 24 h,respectively.Secondly,to investigate the mo-lecular mechanism by which angiotensinⅡ activated PP2A leading to down-regulation eNOS(Ser1177)phosphorylation level,the mesenteric arteries were randomly divided into control group, AngⅡ group and candesartan(CAN; a specific AT1R blocker)+AngⅡgroup.The mesenteric arteries were pretreated with 1×10 -5mol /L CAN for 1 h,then incubated with 1×10 -7mol/L AngⅡfor 12 h in CAN+AngⅡgroup.The protein levels of eNOS,p-eNOS(Ser1177),PP2Ac,p-PP2Ac(Tyr307)and protein phosphatase 2A inhibitor 2(IPP2A2 )in the arteries were determined by Western blot.The ac-tivity of PP2A in the arteries was detected by PP2A activity kit.RESULTS:Compared with the control group,the protein level of p-eNOS(Ser1177)in the mesenteric arteries was decreased after incubated with AngⅡfor 6 h,12 h and 24 h(P<0.05).The decreasing tendency of p-eNOS(Ser1177)showed concentration-dependently,especially in 12 h and 24 h groups.The expression of eNOS protein showed no significant difference in each group.Compared with the control group, the mesenteric arteries of the rats were incubated with AngⅡ at 1×10-7mol/L for 12 h in vitro, the protein levels of p-eNOS(Ser1177)were down-regulated(P<0.05); pretreatment with CAN significantly increased the protein level of p-eNOS(Ser1177)(P<0.05);the protein levels of eNOS showed no significant difference in each group.Compared with the control group,the protein levels of p-PP2Ac(Tyr307)and IPP2A2 were decreased after the mesenteric arteries were trea-ted with AngⅡat 1×10 -7mol/L for 12 h(P<0.05).Candesartan pretreatment restored the protein levels of p-PP2Ac (Tyr307)and IPP2A2 (P<0.05),however the expression of PP2Ac protein showed no significant difference in each group. Compared with the control group,the activity of PP2A was increased in the mesenteric arteries incubated with AngⅡat 1× 10-7mol/L for 12 h(P<0.05).Candesarten pretreatment inhibited the activity of PP 2A significantly(P<0.05).CON-CLUSION:AngⅡincreases PP2A activity via AT1R pathway,thus leading to down-regulation eNOS(Ser1177)phospho-rylation level in mesenteric arteries.The molecular mechanism of PP2A activation may be associated with decreasing the protein levels of p-PP2Ac(Tyr307)and IPP2A2.
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AIM:To explore whether the angiotensin II type 1 receptor autoantibodies(AT1-AA)induces islet β-cell apoptosis and whether autophagy is involved in the process.METHODS:The INS-1 cells treated with AT1-AA at 10-6mol/L for 24 h,and then the apoptosis was analyzed by flow cytometry,Western blot and Hoechst 33258 staining.In addition,the expression of autophagy-related proteins such as LC3 and beclin 1 were determined by Western blot.The effects of AT1-AA on the apoptosis,autophagy and viability of INS-1 cells with or without 3-methyladenine(3-MA;a com-mon autophagy inhibitor)or telmisartan(an angiotensin Ⅱ type 1 receptor blocker)pretreatment, were detected by flow cytometry,Western blot and CCK-8 assay.RESULTS: Treatment with AT1-AA at 10 -6mol/L for 24 h significantly re-duced the cell viability(P<0.05).Compared with the negative IgG control group,the apoptotic cells increased after incu-bation with AT1-AA for 12 h,24 h and 36 h,respectively(P<0.05).Moreover,the protein levels of LC3 and beclin 1 also increased gradually with the prolongation of treatment time,and the elevation of apoptosis and autophagy were blocked by telmisartan.After pretreatment with 3-MA, the apoptotic rate of the cells was obviously decreased compared with the cells treated with AT1-AA alone.CONCLUSION: AT1-AA induces the apoptosis of INS-1 islet βcells by upregulating autophagy via the angiotensin Ⅱtype 1 receptor pathway.
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AIM: To explore the role of imbalance of local renin-angiotensin system (RAS) in lung injury by observing the changes of angiotensin Ⅱ type 1 receptor (AT1R) and Mas receptor protein expression in the lung and the degree of lung injury subject to limb ischemia-reperfusion (LIR) in the mice.METHODS: Male ICR mice (n=42, 8 weeks old) were randomly assigned into 7 groups (6 in each group), including control group and 6 model groups with LIR of 0.5 h, 1 h, 2 h, 4 h, 6 h and 12 h reperfusion.Tourniquets were used to block the blood flow of the hind limbs of the ICR mice and were released after 2 h ischemia to initiate reperfusion.The mice were sacrificed by eyeball blood withdrawal at different time points after reperfusion.The organ coefficient and wet/dry weight ratio (W/D) of the lung tissue were calculated.Bronchoalveolar lavage fluid (BALF) was taken for cell counting and protein concentration measurement.The histopathological changes of the lung tissues was observed, and the pathological score was calculated.The protein expression of AT1R and Mas receptor in the lung tissues was determined by Western blot.RESULTS: The organ coefficient, W/D of lung tissue, and cell number and protein concentration in BALF of model groups were significantly higher than those in control group after LIR.The pathological changes were found in the lung tissue of model mice, including alveolar capillary dilation and congestion, edema, inflammatory cell infiltration in peripheral vascular, alveolar and bronchial walls, alveolar septal thickening and inflammatory cell infiltration.The lung injury score was elevated gradually along with the extension of reperfusion time.The protein expression of AT1R began to increase at reperfusion time points of 0.5 h and 1 h.With the extension of reperfusion time, the protein expression of AT1R decreased gradually.Conversely, the protein expression of Mas receptor increased gradually with prolonged reperfusion.CONCLUSION: LIR induces acute lung injury gradually.The imbalance of AT1R and Mas receptor expression may be involved in the damage process.
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AIM:To investigate whether angiotensin Ⅱ (Ang Ⅱ)/angiotensin Ⅱ type 1 receptor (AT1 R)pathway down-regulates endothelial nitric oxide synthase (eNOS) Ser1177 phosphorylation level in human umbilical vein endothelial cells by activating protein phosphatase 2A (PP2A).METHODS:Human umbilical vein endothelial cells were randomly divided into normal control (control) group,Ang Ⅱ group,candesartan (CAN;specific AT1R blocker) group and CAN pretreatment + Ang Ⅱ group.The protein levels of total eNOS,p-eNOS (Ser1177),PP2Ac,IPP2A2 and p-PP2Ac (Tyr307) were determined by Western blot.The content of NO in the cell culture medium was detected by chemical colorimetry.RESULTS:Compared with control group,the level of p-eNOS (Ser1177) and the content of NO decreased (P ＜0.05).Compared with the same concentration of Ang Ⅱ group,CAN pretreatment increased the level of p-eNOS (Ser1177) and the content of NO (P ＜ 0.05),but the protein expression of eNOS showed no significant difference.Compared with control group,the levels of p-PP2Ac (Tyr307) and IPP2A2 decreased (P ＜ 0.05).Compared with the same concentration of Ang Ⅱ group,CAN pretreatment increased the levels of p-PP2Ac (Tyr307) and IPP2A2 (P ＜ 0.05),but the protein expression of PP2Ac showed no significant difference.CONCLUSION:Ang Ⅱ down-regulates the level of p-eNOS (Ser1177),and decreases the production of NO in human umbilical vein endothelial cells via AT1 R pathway.This effect may be related to the reduction of p-PP2Ac (Tyr307) and protein expression of IPP2A2,which results in the enhancement of PP2A2 activity.Pretreatment with AT1 R blocker CAN increases p-PP2Ac (Tyr307) level and IPP2A2 protein expression,thus reducing the PP2A activity,and ultimately restoring eNOS Ser1177 phosphorylation level and eNOS activity.
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AIM:To investigate whether angiotensin Ⅱ (Ang Ⅱ)/angiotensin Ⅱ type 1 receptor (AT1 R)pathway down-regulates endothelial nitric oxide synthase (eNOS) Ser1177 phosphorylation level in human umbilical vein endothelial cells by activating protein phosphatase 2A (PP2A).METHODS:Human umbilical vein endothelial cells were randomly divided into normal control (control) group,Ang Ⅱ group,candesartan (CAN;specific AT1R blocker) group and CAN pretreatment + Ang Ⅱ group.The protein levels of total eNOS,p-eNOS (Ser1177),PP2Ac,IPP2A2 and p-PP2Ac (Tyr307) were determined by Western blot.The content of NO in the cell culture medium was detected by chemical colorimetry.RESULTS:Compared with control group,the level of p-eNOS (Ser1177) and the content of NO decreased (P ＜0.05).Compared with the same concentration of Ang Ⅱ group,CAN pretreatment increased the level of p-eNOS (Ser1177) and the content of NO (P ＜ 0.05),but the protein expression of eNOS showed no significant difference.Compared with control group,the levels of p-PP2Ac (Tyr307) and IPP2A2 decreased (P ＜ 0.05).Compared with the same concentration of Ang Ⅱ group,CAN pretreatment increased the levels of p-PP2Ac (Tyr307) and IPP2A2 (P ＜ 0.05),but the protein expression of PP2Ac showed no significant difference.CONCLUSION:Ang Ⅱ down-regulates the level of p-eNOS (Ser1177),and decreases the production of NO in human umbilical vein endothelial cells via AT1 R pathway.This effect may be related to the reduction of p-PP2Ac (Tyr307) and protein expression of IPP2A2,which results in the enhancement of PP2A2 activity.Pretreatment with AT1 R blocker CAN increases p-PP2Ac (Tyr307) level and IPP2A2 protein expression,thus reducing the PP2A activity,and ultimately restoring eNOS Ser1177 phosphorylation level and eNOS activity.
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@#AIM: To study the effect of miR-410 on the regulation of angiotensin Ⅱ type 1 receptor(AT1R)in retinal pigment epithelium(RPE)cells of age-related macular degeneration(AMD)patients. <p>METHODS: The experiment was divided into AMD patients, cataract patients and normal people group. AT1R was the target gene of miR-410 by bioinformatics, and the normal RPE cells were cultured in the simulated microenvironment of AMD and cataracts and the expression of miR-410 was detected. Then miR-410 mimics was transfected into cells, and the expression of mRNA and protein of AT1R were detected by Q-PCR and Western blot respectively. The relationship between miR-410 and AT1R was confirmed by the dual luciferase reporter assay. <p>RESULTS: The miR-410 expression of in RPE cells with AMD was significantly reduced(<i>P</i>=0.0006, 0.0008)compared with cataract and normal controls. The miR-410 can regulate the function of AT1R by dual luciferase reporter gene experiment and the inhibition rate was about 40%. In addition, miR-410 inhibition rate was about 40%-50% to AT1R mRNA and protein expression by cell experiment.<p>CONCLUSION: AT1R was a target gene of miR-410 in cell experiments, and it is demonstrated that increasing the expression of miR-410 in RPE cells with AMD can suppress the expression of AT1R.
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Objective To evaluate the effects of renin-angiotensin system (RAS) blockades [angiotensin-converting enzyme inhibitors (ACEI) and angiotensin Ⅱ type 1 receptor blockers (ARB)]on contrast-induced nephropathy (CIN) in patients undergoing angiography.Methods Pubmed,Embase,Cochrane library,Wanfang database and CNKI were searched.The literature limited range was from their start year to July 2015.Randomized controlled trials (RCTs) and non-randomized controlled trials of renin-angiotensin system blockades in influencing CIN were assessed.Two investigators extracted data and performed quality analysis independently from all trims included.Rev man 5.3 software was used.Results 16 trials with a total of 15 897 patients were identified.There were 7490 patients who received renin-angiotensin system blockades and 8407 patients in control group.The meta analysis revealed a higher CIN incidence in ACEI/ARB group than that in control group (14.35％ vs 12.13％,P=0.04,OR=1.44,95％CI 1.01-2.04).For patients with renal insufficiency,ACEI/ARB group had a higher CIN incidence than control group (12.23％ vs 7.32％,P=0.02,OR=1.80,95％CI 1.10-2.94),and the serum creatinine changes in ACEI/ARB group were higher than those in control group.There was statistical difference in serum creatinine changes between groups (P=0.02,MD=0.08,95％CI 0.02-0.15).Conclusions Renin-angiotensin system blockades can increase theincidence of CIN in patients undergoing angiography.Renin-angiotensin system blockades can contribute to CIN for patients with renal insufficiency.
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Objective To evaluate the impact of autoantibodies to angiotensin Ⅱ type 1 receptor AT1-AA on clinic outcomes of delayed graft function (DGF) grafts.Method We reviewed the records of all 139 consecutive adult recipients who received single kidney transplantation and clinical management between Jan.2010 and Dec.2012 in our centre.The serum levels of AT1-AA were measured by a streptavidin-enzyme-linked immunosorbent assay.All patients with DGF were enrolled in this study and divided into two groups:(1) AT+ DGF group (serum AT1-AA positive,11 cases) ;(2) AT-DGF group (serum AT1-AA negative,23 cases).All clinical and laboratory data were recorded in our transplant database system at each visit.Result 139 recipients were enrolled.The overall presence of DGF was 24.5％ (34/139).The incidence of DGF in patients with high binding AT1-AA was significantly higher than that in those with low binding of AT1-AA (11/24 vs.23/115,45.8％ vs.20.0％,P＜0.05).In addition,longer duration of renal replacement therapy (59 ± 32 vs.47 ± 26 months,P＜0.05),higher resistance index (0.80 ± 0.10 vs.0.72 ± 0.10,P＜0.05) of allografts and more severe acute tubular injury (2.7 ± 0.5 vs.1.8 ± 1.1,P＜0.05)/acute tubular necrosis (0.9 ± 0.5 vs.0.5 ± 0.3,P＜0.05) were observed in AT + DGF group than in AT-DGF group.One-year graft survival and death censored graft survival were similar between two groups (90.9％ vs.95.7％,P＞0.05).Conclusion Presence of high binding anti-AT1 receptor had detrimental impacts on initiation and development of DGF.
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Aim To investigate the expression of Notch pathway and Nephrin in angiotensin Ⅱ ( AngⅡ)-stimulated mice podocyte. Methods Mice podo-cyte was stimulated by AngⅡ, and then was treated with valsartan. The levels of Notch1, Notch intracellu-lar domain 1 ( NICD1 ) , Hes1 and Nephrin were deter-mined by immunofluorescence, Western blot and Real-time PCR. Results AngⅡincreased Notch1, NICD1 and Hes1 expression, and decreased Nephrin expres-sion in a time-dependent manner ( P<0. 01 ) . Valsar-tan inhibited AngⅡ-induced activation of Notch path-way and enhanced Nephrin level ( P <0. 01 ) . Con-clusion AngⅡdecreases Nephrin expression in podo-cyte by activating Notch pathway.
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Angiotensin (Ang Ⅱ),a main effector peptide of the renin-angiotensin system (RAS),mediates a hormonal action in the maintenance of blood pressure and electrolyte levels,and thus fluid homeostasis.Recent studies have implicated that it correlates with tumor growth,angiogenesis,metastasis and it has drawn more and more attention.Many studies show that Ang Ⅱ-AT1R/AT2R play crucial roles in tumor growth,metastasis,invasion and tumor angiogenesis,which are formed new targets for treating malignant tumors.
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Objective To compare effects of irbesartan and captopril on left ventricular function in elderly patients with cardiovascular disease and cardiac functional reserve .Methods 100 cases of elderly patients with car-diovascular disease were chosen ,according to a list of numbers randomly divided into the two groups ,50 cases in each group,a group with irbesartan treatment ,as the irbesartan group and the other group received captopril ,as the capto-pril group compared the two groups of patients left ventricular function and cardiac functional reserve .Results (1) Left ventricular function after the irbesartan group therapy LVDd indicators ,IVSd,LVPWd,LVEF,VE/VA,LVM was significantly better than before treatment ,the difference was statistically significant (t=31.23,18.36,28.12,46.36, 51.13,16.03,all P<0.05),the captopril group before and after treatment was significantly better than the treatment of various indicators,the difference was statistically significant (t=24.53,21.36,31.12,14.33,18.19,16.45,all P<0.05);(2) The irbesartan group of patients after treatment resting heart rate ,exercise heart rate,6min walking distance improved significantly over the treatment of former CCRI and CRI ,the difference was statistically significant (t=39.09,23.77,39.01,23.18,22.45,all P<0.05),after treatment with captopril treatment was significantly better than the indexes,the difference was statistically significant (t=91.21,37.16,26.74,46.33,36.74,all P<0.05),6min walking distance from the irbesartan group therapy ,CRI better than the captopril group ,the difference was statistically significant(t=39.02,42.14,all P<0.05).Conclusion Irbesartan and captopril on improving left ventricular function in elderly patients with cardiovascular disease and cardiac reserve function has a significant effect,irbesartan 6min walking distance test and cardiac reserve indices better .
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Objective To explore the relationship between renin-angiotensin system (RAS) blockers and plasma lev-el of adiponectin (APN) in patients with metabolic syndrome (Mets). Methods Fifty-three patients with Mets were random-ized into control group (n=23), angiotensin-convertingenzyme inhibitor (ACEI) group (benidipine, 5 mg/d, n=15) and angio-tensinll recepter blockers(ARB)group (candesartan, 4 mg/d, n=15),and were given 4-week treatment. Twenty-three pa-tients, who were avoiding application related drugs affecting the RAS for four weeks, were used as control. The values of plas-ma APN, fasting blood glucose (FBG), fasting insulin (FINS), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), creatinine(CR), aspartate aminotransferase (ALT), bil-irubin (BIL) and insulin resistance index (HOMA-IR) were detected and compared before and after treatment. Results The levels of FBG and LDL-C were significantly decreased after treatment than those before treatment in ACEI group. The level of CR was significantly lower after treatment than that before treatment in ARB group (P＜0.05). The plasma APN level was significantly higher after treatment compared to that before treatment in ACEI and ARB groups (P＜0.01).There were no sig-nificant differences in the values of FINS,HOMA-IR,TC,ALT and BIL between 'before and after treatment' in three groups (P>0.05). The levels of CR, TC, ALT and BIL before treatment were influencing factors for the APN level. The levels of FBG and TC after treatment were influencing factors for the APN level. Conclusion APN may serve as potential therapeu-tic targets for treating Mets and its related complications by ACEI and ARB.
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Objective To investigate the effect of angiotensin Ⅱ (Ang Ⅱ) type 1 receptor blocker (ARB) on 12-lipoxygenase (12-LO) activity and P-cadherin expression in type 2 diabetic rat glomeruli.Methods Podocytes were stimulated by 107 mol/L Ang Ⅱ for 24 hours.12(S)-HETE (1mg· kg 1 · d-1) and Ang Ⅱ (400 ng· kg-1· min-1) were infused to rats by osmotic mini-pump for 1 week and 2 weeks respectively.Rats fed with high fat diet received low dose streptozotocin (STZ) to make type 2 diabetes and divided into 2 groups:low dose STZ (DN group),low dose STZ + ARB treatment (Losartan group).Rats fed with regular chow were used as control group.All the rats were sacrificed after 6 weeks.Urine,blood,kidney cortical tissue and isolated glomeruli by sieving method were collected at the end of study respectively.ELISA,RT-PCR and Western blotting for related target were performed respectively.Results Ang Ⅱ increased 12(S)-HETE levels in podocytes and glomeruli (all P ＜ 0.01).Ang Ⅱ levels in the glomeruli were significantly increased by 12(S)-HETE stimulation (P ＜0.01).Blood glucose,kidney/body weight and 24 hour urinary protein were increased in DN group compared with that in control group (all P ＜ 0.01).However,urine protein,Kidney/body weight were decreased in Losartan group compared with DN group (all P ＜ 0.05).Increment of 12(S)-HETE content and decrement of P-cadherin expression were observed in DN glomeruli compared with that in control group(all P ＜ 0.01).These abnormalities were prevented by administration of the losartan (all P ＜ 0.05).Conclusions Ang Ⅱ can down-regulate glomerular P-cadherin expression via activation of 12-LO.ARB can ameliorate the progression of DN via up-regulation of glomerular P-cadherin through inhibition of 12-LO activation in type 2 DN rats.
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Objective To identify susceptible miRNAs for the pathogenesis of diabetic nephropathy (DN) and the molecular targets of losartan treatment. Methods The 8-week age KKAy mice were divided into losartan treatment group (10 mg· kg-1· d-1) and non-treatment group,C57BL/6 mice were used as the control group.At age of 20 weeks,body weight,random blood glucose,urinary albumin and urinary creatinine were tested,and kidney morphology was observed.Glomeroli were separated by magnetic beads perfusion,and total RNA were extracted.MiRNAs expression profiles were analyzed by the Affymetrix GeneChip miRNAs arrays. Results At age of 20 weeks,KKAy mice developed higher body weight,higher blood glucose and higher urinary microalbumin creatinine ratio than C57BL/6 mice,and the glomerular basement membrane thickened,mesangial matrix widened.Losartan treatment markedly improved the level of urinary albumin creatinine ratio [(539.71±100.23) mg/g vs (728±177.19) mg/g,P＜0.05)] and pathological lesion of KKAy mice.The miRNA array analysis showed that there were 22 miRNAs differentially expressed between KKAy non-treatment mice and C57BL/6 mice glomeruli at age of 20 weeks.Among them,10 miRNAs were up-regulated,and 12 miRNAs were down-regulated.The expression of 4 miRNAs was down-regulated in glumeruli of KKAy mice treated by losartan compared with that of non-treatment mice.The expressions of miRNA-503 and miRNA-181d were significantly up-regulated in the glumeruli of KKAy mice and inhibited by losartan treatment, Conclusion The expressions of miRNA-503 and miRNA-181d are significantly up-regulated in the glumeruli of KKAy mice and inhibited by losartan treatment,which may be new therapeutic targets of DN.
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Blood pressure remains the single most important modifiable risk factor for the primary and secondary prevention of stroke. The landmark trial of the Perindoprii Protection Against Recurrent Stroke Study (PROGRESS) has suggested that the antihypertensive treatment with angiotensin-converting enzyme inhibitor (ACEI) perindopril at least 2 weeks after stroke may reduce the risks of recurrent stroke and other cardiovascular events. Although most systematic reviews have suggested that the efficacy of almost all types of antihypertensive drugs is similar in the prevention of stroke,there are also some important exceptions. The Ongoing Telmisartan Alone and in Combination with Ramipril Global End point Trial (ONTARGET) has demonstrated that the angiotensin receptor blockers (ARB) telmisartan was equivalent to ramipril for preventing cardiovascular events in patients with vascular disease or diabetes; while in a similar population,ramipril was quite effective for preventing stroke. It is speculated according to the moderating effects of ARB on the renin-angiotensin-aldosterone system that its protective effects against stroke is superior to other antihypertensives. However,many clinical trials have suggested that ARB does not have unique role in stroke prevention. Therefore,whether ARB should be regarded as the first-line drags for stroke prevention in both primary and secondary prevention settings has been controversial.
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Objective To investigate the mechanism of the effects of heavy alcohol consumption in a short term and the protection of angiotensin Ⅱ receptor blocker (valsartan) on cardiac function in rats. Methods The 42 male Wistar rats aged 20 weeks were randomly divided into 4 groups:control group (group C, n= 10), alcohol group (group A, n=10), low-dose valsartan group (LD group, n= 11) and high-dose valsartan group (HD group, n= 11). They were supplied with same animal feeds, but all of them were administered different dose of alcohol and medicine via intragastric tube: group C was administered water, group A was administered alcohol (6. 4 g/kg), LD group was administered alcohol (6.4 g/kg) and valsartan (15 mg/kg), HD group was administered alcohol (6.4 g/kg) and valsartan (30 mg/kg). And 9 weeks later, the change of cardiac function was observed by echocardiography, the body and heart weight were measured, the hydroxyproline content of rat myocardium was determined by sample alkaline solution. Results After 9 weeks, there were no significant differences among four groups in left ventricular ejection fraction (LVEF), stroke volume (SV) and fraction shortening (FS). But the E peak, Ea/Aa, Ea peak and Aa peak were obviously lower in group A than in groups of C, LD and HD (all P＜0.05), and there were significant differences among C group, LD group and HD group in E peak, Ea/Aa (all P＜0. 05). The HW/BW and hydroxproline (Hyp) contents of myocardium were higher in group A than in groups of C, LD and HD (all P＜0. 01), but there were no statistical significances among group C, LD group and HD group (all P＞0. 05). Conclusions The short term heavy alcohol consumption results in impaired ultrastructure and diastolic function of myocardium in rats, the angiotensin Ⅱ receptor blocker (valsartan) may protect it.
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Objective To investigate whether angiotensin Ⅱ type 1 receptor(AT1R)gene polymorphism is associated with essential hypertension(EH). Methods A total of 200 hypertension patients and 192 normotensive controls were enrolled. The AT1R gene 1166A/C and -810A/T polymorphism were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-PFLP), and the association between the SNPs and the EH were analyzed statistically. Some biochemical index such as serum glucose (GLU) and total cholesterol (TC),triglyceride (TG), high density lipoprotein (HDL-C) and low density lipoprotein (LDL-C) were also measured. Results There was no significant difference between two groups of 1166A/C polymorphisms of AT1R gene(P ＞ 0.05 ). However, for the -810A/T polymorphism of AT1R gene, -810 AT and TT genotypes frequencies were significantly higher in EH patients than control (P = 0. 004). The -810T allele frequencies were higher in case than in control (22.5% vs. 11.5% ;P =0.000). We also found an association between EH and -810AT and TT genotypes by logistic regression analysis ( P = 0. 003 ), adjusted for other risk factors. The odds ratio was 2.57 (95% CI:1. 37 ～4. 84). Conclusions AT1R -810A/T polymorphism is associated with EH and -810T allele may be a risk factor of hypertension
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Objective To explore the relationship among genetic polymorphism of angiotension Ⅱ type 1 re-ceptor(AT1 R) A1166-C, angiotensin converting enzyme (ACE) insertion/deletion (I/D), aldosterone synthase (CYP11B2)-344T/C and hypertensive disorder complicating pregnancy.Methods Polymerase chain reaction-re-striction fragment length polymorphism (PCR-RFLP) assay was used to detect the genotypes of AT1 R A1166-C ,ACE (I/O) ,CYP11B2 -344T/C in 86 cases of hypertensive disorder complicating pregnancy and 175 cases of normal control.Results There was 18 combined types in hypertensive disorder complicating pregnancy cases and normal control cases.Compared to AT1R-AA + ACE-Ⅱ + CYP11B2-TT, Odds ratios (OR) of AT1R-AA + ACE-DO +CYP11B2-TC,AT1 R-AC + ACE-ID+CYP11B2-TC and AT1R-AC+ACE-DD+CYP11B2-TC are 7.289,5.315 and 5.694 respectively.There was no statistical significance among the others.Conclusion In all 18 kinds of combined types, AT1 R-AA + ACE-DO + CYP11B2-TC,AT1R-AC+ACE-ID+CYP11B2-TC and AT1 R-AC + ACE-DD +CYP11B2-TC might increase the susceptibility of hypertensive disorder complicating pregnancy.It is possible that multigenes are interacted in the etiology of hypertensive disorder complicating pregnancy.