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AIM: To investigate the possible effect of hyperlipidemia on golmerular podocytes,the nitric oxide synthase (NOS) availability and the synthesis of NOS in podocyte damage by hyperlipidemia,further to study the protective effect of simvastatin on podocytes.METHODS: 4 groups of Wistar rats were fed high fat diet for 18 weeks.Serum lipid,urinary protein excretion and renal pathological changes were detected.Immunohistochemistry was used to determine the expression of desmin.The expression of nNOS was detected by Western blotting.RESULTS: The level of serum lipid was increased significantly in hyperlipidemic group and treated group after 4 weeks (P<0.01) and was decreased significantly in simvastatin treated group compared with hyperlipidemic group (P<0.01).Podocyte injury was detected under electronic microscopy in hyperlipidemic group after 4 weeks,and the injury became more serious during the lasting time.The expression of desmin was increased in hyperlipidemic group after 4 weeks,and the level was significantly decreased in treated groups (P<0.01).The urinary protein excretion was increased significantly after 6 weeks (P<0.01),and the level was significantly lower in treated groups (P<0.01).The expression of nNOS was significantly decreased in hyperlipidemic and treated groups (P<0.01),and the level significantly decreased in simvastatin group (P<0.01).CONCLUSION: Hyperlipidemia induces podocyte injury.The injury seems to be associated with NO deficiency and decreased renal NOS activity.The injury can be relieved by simvastatin. 相似文献
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LI Yao WEI Xin-yi YAN Jun-li WANG Mo WU Dao-qi ZHANG Gao-fu YANG Hai-ping LI Qiu 《园艺学报》2017,33(2):308-314
AIM: To investigate the aggravating effect of albumin overload on the kidney injury induced by lipid nephrotoxicity, and to observe the renoprotective effect of simvastatin (SIMV) on adriamycin nephropathy (ADR) mice.METHODS: SPF healthy male BALB/c mice were randomly divided into control group, ADR group, ADR with bovine serum albumin (BSA) overload (ADR+BSA) group, and ADR with both BSA overload and SIMV treatment (ADR+BSA+SIMV) group. All mice were uninephrectomized under general anesthesia 2 weeks before setting up ADR model. ADR+BSA model started to be set up 4 weeks later. At the end of the 0th, 2nd, 6th, 10th and 14th weeks, 24 h urinary protein was evaluated. At the end of the 14th week, the serum biochemical indexes and the kidney pathological changes were observed, and glomerulosclerotic index (GSI) was also evaluated. The cholesterol in the kidney was measured by enzymic colorimetric method and oil red O staining. The expression of IL-1β, TGF-β1 and low-density lipoprotein receptor (LDLr) in the kidney tissues was determined by real-time PCR. The expression of IL-1β and IL-17 was measured by immunohistochemistry and the expression of IL-17 in the kidney was measured by ELISA.RESULTS: Compared with control group, the expression of IL-1β, TGF-β1, IL-17 and LDLr, and cholesterol content in the kidney and the GSI were all significantly increased in ADR group (P<0.05). Compared with ADR group, 24 h urinary protein, serum creatinine, the expression of IL-1β, IL-17 and LDLr, and cholesterol content in the kidney were all significantly increased in ADR+BSA group (P<0.05). Treatment with SIMV significantly decreased the expression of IL-1β, TGF-β1, IL-17 and LDLr. The accumulation of cholesterol in the kidney and the GSI were also decreased (all P<0.05).CONCLUSION: Inflammation aggravates the lipid deposition and glomerular sclerosis by increasing the expression of LDLr in ADR mice. Albumin overload further accelerates the progressive kidney damage by regulating the expression of IL-1β, TGF-β1 and IL-17, which promotes the increase in LDLr. The beneficial effect of SIMV might be mediated by its anti-inflammatory effect. 相似文献
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AIM: To observe the influence of simvastatin on insulin secretion function of mouse pancreatic beta cell line MIN6 and to explore its possible mechanisms.
METHODS: MIN6 cells were randomly divided into normal control group and low-, middle-and high-concentration simvastatin treatment groups, which were cultured for 48 h with high-glucose DMEM containing 15% fetal bovine serum plus 0, 2, 5 and 10 μmol/L simvastatin, respectively. The insulin secretion of MIN6 cells was measured by radioimmunoassay. The content of ATP in MIN6 cells was measured by biochemiluminescence method. The mRNA and protein expression levels of inwardly rectifying potassium channel 6.2 (Kir6.2), voltage-dependent calcium channel 1.2 (CaV1.2) and glucose transporter 2 (GLUT2) were detected by real-time fluorescence quantitative PCR and Western blotting, respectively.
RESULTS: Compared with normal control group, middle-and high-concentration simvastatin treatment markedly decreased the synthesis and secretion of insulin in MIN6 cells (P<005). The content of ATP in MIN6 cells was markedly decreased in simvastatin treatment groups (P<005). The mRNA expression level of Kir6.2 in MIN6 cells was significantly up-regulated in simvastatin treatment groups (P<001), while the mRNA expression levels of CaV1.2 and GLUT2 were significantly down-regulated in middle-and high-concentration simvastatin treatment groups (P<001). The protein expression of Kir6.2 was significantly increased but that of CaV1.2 was significantly decreased in middle-and high-concentration simvastatin treatment groups (P<001), and the protein expression level of GLUT2 was markedly decreased in high-concentration simvastatin treatment group (P<001).
CONCLUSION: Simvastatin inhibits insulin synthesis and secretion in mouse pancreatic beta cell line MIN6 via suppressing ATP production, up-regulating the expression of Kir6.2 and down-regulating the expression of CaV1.2 and GLUT2. 相似文献
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AIM:Hydroxymethylglutaryl CoA (HMG-CoA) reductase inhibitors, such as simvastatin, have been shown to reduce atherosclerotic cardiovascular morbidity and mortality by mechanisms unrelated to its lipid-lowering effect. Several studies have shown that simvastatin induces apoptosis in a varieties of cell lines including vascular smooth muscle cells (VSMC). The aim of this study was to investigate the signal pathways involved in apoptosis induced by simvastatin.METHODS:Cultured VSMC were treated with simvastatin. Calpain activity was determined by measuring Ca2+ ionophore-specific calpain substrate (suc-LLVY-AMC), caspase-3 activation was detected by Western blot, and apoptotic changes were distinguished by annexin Ⅴ binding and DNA laddering.RESULTS:After incubated with 30 μmol/L simvastatin for 8 h, calpain activity had a marked increase (P<0.05, n=4) and reached to more than 3-fold of control at 12 h (P＜0.01). Caspase-3 also activated by simvastatin after 12 h. PD150606, a cell-permeable selective calpain inhibitor, decreased simvastatin-induced apoptosis rate from 24.2%±1.7% to 9.5%±1.9% (P＜0.01) and also prevented simvastatin-induced DNA laddering. Furthermore, 100 μmol/L PD150606 efficiently inhibited simvastatin-induced caspase-3 activation.CONCLUSION:Simvastatin induces apoptosis by activating caspase-3 via calcium-dependent protease calpain. 相似文献
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WU Jun WANG Lian-sheng CHEN Min-sheng SUN Ming ZHOU Hong-yan XU Hui ZHOU Hong-hao 《园艺学报》2003,19(10):1341-1344
AIM:To study the impact of hyperlipidemia on aortic AT1 mRNA expression and vasoactive substances, and investigate the potential mechanism on reversion of endothelial dysfunction during the statin therapy.METHODS:The investigation included control, hyperlipidemic and simvastatin-treated groups. Hyperlipidemic model was set up on the 4-week atherogenic diet, followed by a 16-week treatment in the simvastatin treated group (simvastatin 10 mg·kg-1·d-1) and without treatment in the hyperlipidemic group. Serum lipid level, the expression of AT1mRNA of aorta and level of serum AngⅡ and nitric oxide (NO) were measured. RESULTS: Compared with the control group, hyperlipidemic rats showed a stronger expression of AT1 mRNA and lower level of NO. No significant difference in systolic blood pressure and AngⅡ was showed in this group. In contrast, in simvastatin treated group, expression of AT1 mRNA as well as lipid(TC, TG, LDL-C) levels were significantly decreased and NO level increased which associated with improvement of endothelial dysfunction. CONCLUSION:By regulated the lipid level, downregulated AT1 mRNA expresstion and increased the NO activity, simvastatin restored endothelial function and inhibited atherogenesis. 相似文献
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AIM: To investigate the effect of simvastatin (SMV) on tumor necrosis factor α (TNF-α)-induced chemokine secretion in rheumatoid arthritis fibroblast-like synoviocytes (RA FLS).METHODS: RhoA activity was determined by pull-down assay. Chemokine secretion was measured by ELISA. MTT test was used to detect cell viability.RESULTS: Simvastatin attenuated TNF-α-induced interleukin-8(IL-8) and monocyte chemotactic protein-1(MCP-1) secretion as well as RhoA activation in RA FLS. The inhibitory effects of SMV were completely reversed by mevalonate (MEVA) and geranylgeranyl pyrophosphate (GGPP). Suppression of RhoA activation with a specific inhibitor depressed the secretion of IL-8 and MCP-1 in TNF-α-induced RA FLS.CONCLUSION: Simvastatin inhibits TNF-α-induced secretion of IL-8 and MCP-1 in RA FLS through inhibition of RhoA activation, indicating a novel strategy for anti-inflammatory effects of statins on treatment of RA. 相似文献
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YIN Ming-jing WEN Han-chun YE Yong-wei GUAN Qing-lin HUANG Hao-zhang HUANG Lu-shuang ZHU Ji-jin 《园艺学报》2012,28(2):228-233
AIM: To investigate the effect of simvastatin intervention on the changes of blood pressure, serum lipid fluctuation and aortic configuration induced by high-sodium and high-fat diet in rats. METHODS: Sixty adult male SD rats were randomly divided into 5 groups (n=12): control (N)group, high salt (S)group, high fat (F) group, high salt+ high fat (SF) group and high salt+high fat + simvastatin (T) group. After fed for 16 weeks, the rats were subject to determine blood pressures and serum concentrations of triglycerides (TG),total cholesterol(TC) and soluble CD40 ligand (sCD40L). The expression of CD40/CD40L in the root of ascending aorta was detected by immunohistochemical method. The thickness of intima media in the ascending aorta as well as the ratio of lumen area/total vascular area were measured and calculated after HE staining. RESULTS: In S group, F group and SF group, systolic blood pressure was significantly higher than that in N group (P<0.01). Systolic blood pressure in T group were slightly higher than that in N group with statistical significance and significantly lower than that in SF group. The serum concentrations of TG and TC in F group and SF group were significantly higher than those in N group and T group (P<0.01), and no significant difference among S group, N group and T group was observed. In S group, F group and SF group, the serum concentrations of sCD40L were higher than that in N group and T group (P<0.05), meanwhile that in SF group was also higher than that in S group and F group (P<0.05). However, no significant difference of sCD40L concentration between S group and F group as well as N group and T group was observed. The expression of CD40/CD40L in the ascending aorta in S group, F group and SF group was higher than that in N group and T group (P<0.05), and that in SF group was also higher than that in S group and F group (P<0.05).No significant difference of CD40/CD40L expression between S group and F group as well as N group and T group was observed. The thickness of intima media in S group, F group and SF group was significantly thicker than that in N group (P<0.01), and no significant difference of the intima media thickness between T group and N group was observed. The ratio of lumen area/total vascular area in S group, F group and SF group was smaller than that in N group (P<0.05), and no significant difference of the ratio between T group and N group was found. CONCLUSION: Feeding high-fat and high-salt diet leads to blood pressure elevation, induces atherosclerosis, increases serum concentration of sCD40L and enhances the expression of CD40/CD40L in arterial tissues. The combination of the stimuli has stronger effect than a single factor. Statins protect the arterial tissues against atherosclerosis by decreasing the level of serum sCD40L and inhibiting the arterial expression of CD40/CD40L. 相似文献
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AIM: To investigate the effects of simvastatin on the expression of Toll-like receptor 2 (TLR-2), interferon-γ (IFN-γ) and monocyte chemoattractant protein-1 (MCP-1) in lung tissues of mice with mouse cytomegalovirus (MCMV) pneumonia and to explore the possible mechanism. METHODS: Male BALB/c mice (6~8 weeks old, n=40) were randomly divided into 5 groups: normal control (NC) group, MCMV infection group, simvastatin group 1 (SMV1 group), simvastatin group 2 (SMV2 group), and simvastatin group 3 (SMV3 group). The mice in SMV1, SMV2 and SMV3 groups were gavaged with simvastatin (50 mg·kg-1·d-1 for 7 d) 7 d before, on the same day of and 3 d after intraperitoneal injection of MCMV, while the mice in normal control group and MCMV infection group were gavaged with the same volume of normal saline. HE staining was used to observe the pathological changes of lung tissues in mice. Total tissue protein was extracted from the lung homogenates to detect the expression of TLR-2 by Western blot and immunohistochemical staining. Real-time PCR was used to analyse the content of MCMV DNA. The levels of IFN-γ and MCP-1 were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared with NC group, the pathological changes of the lung tissues of the mice in MCMV group showed alveolar interstitial edema, alveolar wall widening and a large number of inflammatory cells. The expression of TLR-2 in the lung tissues of the mice in model group was increased significantly. The content of MCMV DNA was increased, and the expression of IFN-γ and MCP-1 was also increased significantly. Compared with the mice in MCMV group, the pathological changes of the lung tissues of simvastatin groups showed that the inflammatory cells were decreased. The expression of TLR-2 was down-regulated. The content of MCMV DNA was decreased, and the levels of IFN-γ and MCP-1 were also decreased significantly. At the same time, the expression of TLR-2 and the content of MCMV DNA in SMV1 group were less than those in SMV2 and SMV3 groups (P<0.05), and no statistically significant difference between SMV2 and SMV3 groups was observed. CONCLUSION: Simvastatin down-regulates the TLR-2 signaling pathway, and reduces the expression of TLR-2 and replication of MCMV DNA, thus attenuating the pathological damage of the lung tissue. Early intervention with simvastatin plays an important role in preventing the infection of MCMV and reducing the inflammation. 相似文献
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