Metabolic syndrome (MS) has been defined by the presence of a cluster of most dangerous risk factors, such as insulin resistance, hyperinsulinemia, and some combination of dyslipidemia and hypertension.1) Global lifestyle changes, including an increase in caloric intake and a reduction in physical activity, have sharply increased the number of patients with MS.2) Clinical studies reported that MS also increases the risk for proteinuria and chronic kidney disease independent of diabetes and hypertension.3,4) However, the underlying mechanisms and efficient therapy of nephropathy associated with MS are not completely elucidated.Chronic consumption of high-fat, high-sucrose diet induces a MS model in normal rats, which is associated with dyslipidemia, hypertension, obesity, and insulin resistance. 5,6) However, damages of renal structure and function have not been reported in this MS model. In fact, whether high-fat or high-fat, high-sucrose diet produced renal functional and pathological lesions is still conflicting.7,8) Nevertheless, several studies have demonstrated that high salt diet induces slightly hyperinsulinemia, moderately hypertension and renal damages in Sprague-Dawley (SD) rats.9-11) Therefore, we hypothesized that long-term consumption of a high-fat, highsalt diet and sucrose solution in SD rats could induce a suitable animal model that mimics the basic characteristics of human MS and is helpful to understand the pathogenesis and therapy of nephropathy associated with MS.Clinical and experimental studies have shown that losartan (angiotensin II receptor blocker, ARB) and pioglitazone (peroxisome proliferator-activated receptor-g, PPARg agonist) have renoprotective effects in diabetic nephropathy (DN) and non-diabetic renal diseases.12-16) In addition, a recent study demonstrated that losartan and pioglitazone have synergistic renoprotective actions in patients with type 2 DN. 14) However, to our knowledge, there was no study on comparing the effects of losartan and pioglitazone combination therapy with monotherapy in MS nephropathy rats.Vascular endothelial growth factor (VEGF) is an important growth factor involved in neoangiogenesis and vascular trophism. The dysregulation of VEGF signaling system has been identified in a wide variety of renal diseases, such as DN, glomerulonephritis, acute renal failure, chronic renal disease, and so on. [17][18][19] Qin et al. 13) suggested that losartan attenuates the overexpression of VEGF in DN rats. Lee et al. 20) demonstrated that pioglitazone has beneficial effects on DN in Otsuka-Long-Evans-Tokushima-Fatty rats by reducing the VEGF expression. Thus, we speculated that both drugs might improve renal damage in this MS model through attenuating dysregulation of the VEGF expression.Therefore, the purposes of this study were: first, to establish a suitable animal model of nephropathy associated with MS; second, to evaluate the possible benefits of losartan and pioglitazone in this experimental MS nephropathy rats; third, to assess whether the combination ...
We recently showed that combination therapy with losartan and pioglitazone provided synergistic effects compared with monotherapy in improving lesions of renal structure and function in Sprague-Dawley rats fed with a high-fat, high-sodium diet and 20% sucrose solution. This study was designed to explore the underlying mechanisms of additive renoprotection provided by combination therapy. Losartan, pioglitazone, and their combination were orally administered for 8 weeks. The increased level of renal malondialdehyde and expression of nicotinamide adenine dinucleotide phosphate oxidase subunit p47phox and nitrotyrosine as well as the decreased total superoxide dismutase activity and copper, zinc-superoxide dismutase expression were tangible evidence for the presence of oxidative and nitrative stress in the kidney of model rats. Treatment with both drugs, individually and in combination, improved these abnormal changes. Combination therapy showed synergistic effects in reducing malondialdehyde level, p47phox, and nitrotyrosine expression to almost the normal level compared with monotherapy. All these results suggest that the additive renoprotection provided by combination therapy might be attributed to a further reduction of oxidative and nitrative stress.
Introduction: This study was designed to investigate the underlying mechanisms of synergistic antihypertensive effect produced by combination therapy of losartan and pioglitazone in metabolic syndrome (MS) rats. Materials and methods: An MS model was induced by feeding rats a high-fat, high-sodium diet and 20% sucrose solution. Losartan (20 mg/kg/day), pioglitazone (10 mg/kg/day), and their combination were orally administered for eight consecutive weeks. Systolic blood pressure (SBP) and mean arterial pressure (MAP) were measured using the tail-cuff method and carotid arterial catheterization, respectively. The aortas were isolated and in vitro vascular reactivity studies were performed. The protein expression of angiotensin type 1 receptor (AT 1 ), endothelial nitric oxide synthase (eNOS), phosphorylated eNOS and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47 phox , level of nitrotyrosine as well as activity of eNOS and NADPH oxidase in aortas of MS rats were detected. Results: After eight weeks of treatment, the SBP and MAP in the losartan (115 ± 5 and 106 ± 6 mmHg), pioglitazone (130 ± 6 and 118 ± 6 mmHg), and combination therapy (105 ± 6 and 98 ± 5 mmHg) groups were lower than those in the model group (150 ± 8 and 136 ± 9 mmHg). Combination therapy of losartan and pioglitazone reduced BP more than either monotherapy, and showed additive effects on improving endothelial dysfunction and abolishing the increased vascular responsiveness to angiotensin II. These synergistic effects were associated with further reductions in protein expression of p47 phox and AT 1 , NADPH oxidase activity, and nitrotyrosine level. Conclusions: Our data indicate that combined treatment exerts more beneficial effects on lowering BP and improving vascular lesions.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.