Exendin-4 has an anti-hypertensive effect in salt-sensitive mice model

Department of Medicine, Shiga University of Medical Science, Tsukinowa-cho, Seta, Otsu, Shiga 520-2192, Japan.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 02/2009; 380(1):44-9. DOI: 10.1016/j.bbrc.2009.01.003
Source: PubMed


The improvement of salt-sensitive hypertension is a therapeutic target for various vascular diseases. Glucagon-like peptide 1 (GLP-1), an incretin peptide, has been reported to have natriuretic effect as well as blood glucose lowering effect, although its exact mechanism and clinical usefulness remain unclear. Here, we examined anti-hypertensive effect of exendin-4, a GLP-1 analog, in salt-sensitive obese db/db mice and angiotensin II (angII)-infused C57BLK6/J mice. The treatment of exendin-4 for 12 weeks inhibited the development of hypertension in db/db mice. In db/db mice, the urinary sodium excretion was delayed and blood pressure was elevated in response to a high-salt load, whereas these were attenuated by exendin-4. In db/db mice, intra-renal angII concentration was increased. Furthermore, exendin-4 prevented angII-induced hypertension in non-diabetic mice and inhibited angII-induced phosphorylation of ERK1/2 in cultured renal cells. Considered together, our results indicate that exendin-4 has anti-hypertensive effects through the attenuation of angII-induced high-salt sensitivity.

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Available from: Shinji Kume, Feb 03, 2014
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    • "GLP-1R agonists, such as exendin-4 and liraglutide , are new therapy options for type 2 diabetes, and produced substantial and clinically significant reductions in HbA1c and fasting and postprandial glucose levels with moderate weight loss (Nauck et al. 2009). With respect to the effects of GLP-1 on the kidney, it has been reported that in animal model, GLP-1R agonists have various extra-pancreatic actions such as regulating sodium excretion in the tubular cells of the kidney (Hirata et al. 2009) and they have been shown to directly prevent the progression of DN through the suppression of inflammatory process via the activation of GLP-1R in kidney tissue (Kodera et al. 2011). Furthermore, GLP-1 is rapidly degraded in the body by dipeptidylpeptidase (DPP) IV. "
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    ABSTRACT: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Glucagon-like peptide-1 (GLP-1) is one of the incretins, gut hormones released from the intestine in response to food intake. GLP-1 receptor (GLP-1R) agonists have been used to treat type 2 diabetes. Here, we studied the effect of the administration of a GLP-1R agonist, liraglutide, on proteinuria and the progression of overt DN in type 2 diabetic patients. Twenty-three type 2 diabetic patients with overt DN, who had already been treated with blockade of renin-angiotensin system under dietary sodium restriction, were given liraglutide for a period of 12 months. Treatment with liraglutide caused a significant decrease in HbA1c from 7.4 ± 0.2% to 6.9 ± 0.3% (p = 0.04), and in body mass index (BMI) from 27.6 ± 0.9 kg/m(2) to 26.5 ± 0.8 kg/m(2) after 12 months (p < 0.001), while systolic blood pressure did not change. The progression of DN was determined as the rate of decline in estimated glomerular filtration rate (eGFR). The 12-month administration of liraglutide caused a significant decrease in proteinuria from 2.53 ± 0.48 g/g creatinine to 1.47 ± 0.28 g/g creatinine (p = 0.002). The administration of liraglutide also substantially diminished the rate of decline in eGFR from 6.6 ± 1.5 mL/min/1.73 m(2)/year to 0.3 ± 1.9 mL/min/1.73 m(2)/year (p = 0.003). Liraglutide can be used not only for reducing HbA1c and BMI, but also for attenuating the progression of nephropathy in type 2 diabetic patients.
    Full-text · Article · Aug 2013 · The Tohoku Journal of Experimental Medicine
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    • "The mechanism for lowering blood pressure by exenatide appears to be related to weight loss. However, in salt-sensitive rodent models, GLP-1 treatment has been shown to have antihypertensive, cardioprotective, and renoprotective actions through natriuretic and diuretic effects [48]. As discussed previously, the action on endothelium and vascular smooth muscle, producing vasodilatory effects, may contribute to lowering of the blood pressure [9, 10]. "
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    ABSTRACT: Type 2 diabetes mellitus (T2DM) is a well-recognized risk factor for the development of cardiovascular disease. With an increasing prevalence of obesity, this risk has increased further. Management of T2DM in obese patients is particularly challenging as treatment with the majority of glucose-lowering agents results in weight gain. Thus, the development of a therapeutic option which could improve glycemic control without weight gain or hypoglycemia, such as the glucagon-like peptide-1 (GLP-1) analog exenatide, is a welcome addition to the currently available therapies in the management of T2DM. With recognition and better understanding of the role of incretin hormones in T2DM, exenatide was developed and introduced into clinical practice in 2005. Both randomized controlled trials and retrospective observational studies have shown that treatment with exenatide not only improves glycemic control, with a low risk of hypoglycemia, but also results in concurrent weight loss and the additional benefit of improvement in cardiovascular risk factors. This article will provide an overview of both short- and long-acting exenatide in the management of T2DM and associated cardiovascular risk factors.
    Preview · Article · Nov 2012 · Diabetes Therapy
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    • "Previously, GLP-1R activation by exendin-4 was shown to inhibit Ang II activation in renal proximal tubular cells (22). Our results demonstrate that GLP-1 is partly mediating its protective action via its own receptor by the activation of PKA. "
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    ABSTRACT: To characterize glucagon-like peptide (GLP)-1 signaling and its effect on renal endothelial dysfunction and glomerulopathy. We studied the expression and signaling of GLP-1 receptor (GLP-1R) on glomerular endothelial cells and the novel finding of protein kinase A-dependent phosphorylation of c-Raf at Ser259 and its inhibition of angiotensin II (Ang II) phospho-c-Raf(Ser338) and Erk1/2 phosphorylation. Mice overexpressing protein kinase C (PKC)β2 in endothelial cells (EC-PKCβ2Tg) were established. Ang II and GLP-1 actions in glomerular endothelial cells were analyzed with small interfering RNA of GLP-1R. PKCβ isoform activation induced by diabetes decreased GLP-1R expression and protective action on the renal endothelium by increasing its degradation via ubiquitination and enhancing phospho-c-Raf(Ser338) and Ang II activation of phospho-Erk1/2. EC-PKCβ2Tg mice exhibited decreased GLP-1R expression and increased phospho-c-Raf(Ser338), leading to enhanced effects of Ang II. Diabetic EC-PKCβ2Tg mice exhibited greater loss of endothelial GLP-1R expression and exendin-4-protective actions and exhibited more albuminuria and mesangial expansion than diabetic controls. These results showed that the renal protective effects of GLP-1 were mediated via the inhibition of Ang II actions on cRaf(Ser259) and diminished by diabetes because of PKCβ activation and the increased degradation of GLP-1R in the glomerular endothelial cells.
    Full-text · Article · Jul 2012 · Diabetes
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