19 research outputs found

    Add-on effect of probucol in atherosclerotic, cholesterol-fed rabbits treated with atorvastatin.

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    OBJECTIVE: Lowering the blood concentration of low-density lipoprotein (LDL) cholesterol is the primary strategy employed in treating atherosclerotic disorders; however, most commonly prescribed statins prevent cardiovascular events in just 30% to 40% of treated patients. Therefore, additional treatment is required for patients in whom statins have been ineffective. In this study of atherosclerosis in rabbits, we examined the effect of probucol, a lipid-lowering drug with potent antioxidative effects, added to treatment with atorvastatin. METHODS AND RESULTS: Atherosclerosis was induced by feeding rabbits chow containing 0.5% cholesterol for 8 weeks. Probucol 0.1%, atorvastatin 0.001%, and atorvastatin 0.003% were administered solely or in combination for 6 weeks, beginning 2 weeks after the start of atherosclerosis induction. Atorvastatin decreased the plasma concentration of non-high-density lipoprotein cholesterol (non-HDLC) dose-dependently; atorvastatin 0.003% decreased the plasma concentration of non-HDLC by 25% and the area of atherosclerotic lesions by 21%. Probucol decreased the plasma concentration of non-HDLC to the same extent as atorvastatin (i.e., by 22%) and the area of atherosclerotic lesions by 41%. Probucol with 0.003% atorvastatin decreased the plasma concentration of non-HDLC by 38% and the area of atherosclerotic lesions by 61%. Co-administration of probucol with atorvastatin did not affect the antioxidative effects of probucol, which were not evident on treatment with atorvastatin alone, such as prevention of in vitro LDL-oxidation, increase in paraoxonase-1 activity of HDL, and decreases in plasma and plaque levels of oxidized-LDL in vivo. CONCLUSIONS: Probucol has significant add-on anti-atherosclerotic effects when combined with atorvastatin treatment; suggesting that this combination might be beneficial for treatment of atherosclerosis

    An Atherogenic Paigen-Diet Aggravates Nephropathy in Type 2 Diabetic OLETF Rats

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    <div><p>Diabetic nephropathy develops in association with hyperglycemia, is aggravated by atherogenic factors such as dyslipidemia, and is sometimes initiated before obvious hyperglycemia is seen. However, the precise mechanisms of progression are still unclear. In this study, we investigated the influence of an atherogenic Paigen diet (PD) on the progression of nephropathy in spontaneous type 2 diabetic OLETF rats. Feeding PD to male OLETF rats for 12 weeks caused an extensive increase in excretion of urinary albumin and markers of tubular injury such as KIM-1 and L-FABP, accompanied by mesangial expansion and tubular atrophy. PD significantly increased plasma total cholesterol concentration, which correlates well with increases in urine albumin excretion and mesangial expansion. Conversely, PD did not change plasma glucose and free fatty acid concentrations. PD enhanced renal levels of mRNA for inflammatory molecules such as KIM-1, MCP-1, TLR4 and TNF-α and promoted macrophage infiltration and lipid accumulation in the tubulointerstitium and glomeruli in OLETF rats. Intriguingly, PD had little effect on urine albumin excretion and renal morphology in normal control LETO rats. This model may be useful in studying the complex mechanisms that aggravate diabetic nephropathy in an atherogenic environment.</p></div

    Immunohistochemical analysis of kidneys in LETO and OLETF rats.

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    <p>Representative immunohistochemical images of glomerular, tubular and tubulointerstitial lesions in each group, 12 weeks after starting to feed a Paigen diet. Scale bar, 100 μm. KIM-1, kidney injury molecule-1; MRP8, myeloid-related protein 8; NOX2, NADPH oxidase 2; OPN, osteopontin; TLR4, toll-like receptor 4; TNF-α, tumor necrosis factor-α.</p

    High-fat and cholate in a Paigen diet synergistically worsen the nephropathy of OLETF rats.

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    <p>Time-dependent changes in urine albumin excretion (A), glomerular sclerosis index (B) and plasma total cholesterol (TC) concentration (C) 5 weeks after starting to feed each diet are presented as mean ± SD (n = 8). Relationships between plasma TC concentration and urine albumin secretion or glomerular sclerosis index are shown in D. *p < 0.05; **p < 0.01; ns, not significant by Dunnett’s test. ††p < 0.01 of the interaction effect analyzed by two-way ANOVA. Spearman correlation coefficient (r) was calculated and a test of no correlation was performed.</p

    Plasma lipoprotein profiles in LETO and OLETF rats.

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    <p>Plasma lipoprotein profiles of rats aged 6 (OLETF-PD-1d), 9 (OLETF-PD-3w) and 18 weeks (LETO-NC, OLETF-NC and OLETF-PD-12w) were analyzed by HPLC using the pooled plasma of each group. CM, chylomicron; HDL, high-density lipoprotein; LDL, low-density lipoprotein; VLDL, very low-density lipoprotein.</p

    Histological analysis of kidneys in LETO and OLETF rats.

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    <p>(A) Representative histological images are shown of glomerular, tubular and tubulointerstitial lesions of each group 12 weeks after the start of Paigen diet feeding. Scale bar, 100 μm. Glomerular volume (B), glomerular sclerosis index (C) and macrophage (CD68)-positive cells in glomeruli (D) are presented as mean ± SD. There were five animals in the group of LETO rats fed normal chow (LETO-NC), eight in the group of OLETF rats fed normal chow (OLETF-NC), and 11 in the group of OLETF rats fed a Paigen diet (OLETF-PD). #p < 0.05; ##p < 0.01; NS, not significant by unpaired t-test. ORO, Oil red O stain; PAS, periodic acid schiff stain.</p

    mRNA levels in kidneys of LETO and OLETF rats.

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    <p>The mRNA levels in kidneys of LETO and OLETF rats, 12 weeks after the start of Paigen diet feeding, are presented as mean ± SD. There were five animals in the group of LETO rats fed normal chow (LETO-NC), eight in the group of OLETF rats fed normal chow (OLETF-NC), and 12 in the group of OLETF rats fed a Paigen diet (OLETF-PD). #p < 0.05; ##p < 0.01; NS, not significant by unpaired t-test. Col4a1, procollagen type IV 4α; Gpx2, glutathione peroxidase 2; HIF-1α, hypoxia inducible factor 1α; HO-1, heme oxygenase 1; IL-1β, interleukin-1β; KIM-1, kidney injury molecule-1; MCP-1, monocyte chemoattractant protein-1; MRP8, myeloid-related protein 8; NOX2, NADPH oxidase 2; NOX4, NADPH oxidase 4; TGF-β, transforming growth factor-β; TLR4, toll-like receptor 4; TNF-α, tumor necrosis factor-α; VCAM-1, vascular cell adhesion molecule-1.</p

    Time-dependent changes in urine excretion of tubule injury markers.

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    <p>Changes in urinary excretion of albumin, liver fatty-acid-binding protein (L-FABP), cystatin C, N-acetyl-β-D-glucosaminidase (NAG), and kidney injury molecule-1 (KIM-1) after starting to feed a Paigen diet in OLETF rats are presented as mean ± SD. (A) Changes between baseline and the day after starting to feed a Paigen diet in OLETF rats (n = 11). (B) Time-dependent changes from baseline to 12 weeks after the start of normal chow or Paigen diet feeding. There were five animals in the group of LETO rats fed normal chow (LETO-NC), eight in the group of OLETF rats fed normal chow (OLETF-NC), and 12 in the group of OLETF rats fed a Paigen diet (OLETF-PD). ‡‡p < 0.01; NS, not significant by paired t-test. *p < 0.05; **p < 0.01 vs LETO-NC group and #p < 0.05; ##p < 0.01 vs OLETF-NC group by unpaired t-test.</p

    An atherogenic Paigen-diet worsens the nephropathy of OLETF rats.

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    <p>Time-dependent changes in urine albumin excretion (A), semi-quantitative analyses of glomerular sclerosis (B) and plasma lipids and glucose concentrations (C) 12 weeks after starting to feed chow or an atherogenic diet, presented as mean ± SD. There were five animals in the following groups: LETO rats fed normal chow (LETO-NC) and Paigen diet (LETO-PD), and OLETF rats fed NC (OLETF-NC) and Western diet (OLETF-WD); and nine in the OLETF rats fed PD (OLETF-PD) groups. *p < 0.05; **p < 0.01; ns, not significant vs OLETF-NC group among three OLETF groups by Dunnett’s test. #p < 0.05; ##p < 0.01; NS, not significant by unpaired t-test. There were no significant differences between LETO-NC and LETO-PD or LETO-NC and OLETF-NC groups in urine albumin (unpaired t-test). TC, total cholesterol; TG, triacylglycerol.</p
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