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: 2.28). 02/2009; 380(1):44-9. DOI: 10.1016/j.bbrc.2009.01.003
Source: PubMed

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Incretin-based drugs, i.e., glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, are widely used for the treatment of type 2 diabetes. In addition to the primary role of incretins in stimulating insulin secretion from pancreatic β-cells, they have extra pancreatic functions beyond glycemic control. Indeed, recent studies highlight the potential beneficial effects of incretin-based therapy in diabetic kidney disease (DKD). Experimental studies using various diabetic models suggest that incretins protect the vascular endothelium from injury by binding to GLP-1 receptors, thereby ameliorating oxidative stress and the local inflammatory response, which reduces albuminuria and inhibits glomerular sclerosis. In addition, there is some evidence that GLP-1 receptor agonists and DPP-4 inhibitors mediate sodium excretion and diuresis to lower blood pressure. The pleiotropic actions of DPP-4 inhibitors are ascribed primarily to their effects on GLP-1 signaling, but other substrates of DPP-4, such as brain natriuretic peptide and stromal-derived factor-1α, may have roles. In this review, we summarize recent studies of the roles of incretin-based therapy in ameliorating DKD and its complications.Kidney International advance online publication, 9 July 2014; doi:10.1038/ki.2014.236.
    Kidney International 07/2014; 86(4). DOI:10.1038/ki.2014.236 · 8.52 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Despite the beneficial effects of type 4 dipeptidyl peptidase (DPP-4) inhibitors on glucose levels, its effects on diabetic nephropathy remain unclear. Method: This study examined the long-term renoprotective effects of DPP-4 inhibitor linagliptin in db/db mice, a model of type 2 diabetes. Results were compared with the known beneficial effects of renin-angiotensin system blockade by enalapril. Ten-week-old male diabetic db/db mice were treated for 3 months with either vehicle (n = 10), 3 mg linagliptin/kg per day (n = 8), or 20 mg enalapril/kg per day (n = 10). Heterozygous db/m mice treated with vehicle served as healthy controls (n = 8). Results: Neither linagliptin nor enalapril had significant effects on the parameters of glucose metabolism or blood pressure in diabetic db/db mice. However, linagliptin treatment reduced albuminuria and attenuated kidney injury. In addition, expression of podocyte marker podocalyxin was normalized. We also analysed DPP-4 expression by immunofluorescence in human kidney biopsies and detected upregulation of DPP-4 in the glomeruli of patients with diabetic nephropathy, suggesting that our findings might be of relevance for human kidney disease as well. Conclusion: Treatment with DPP-4 inhibitor linagliptin delays the progression of diabetic nephropathy damage in a glucose-independent and blood-pressure-independent manner. The observed effects may be because of the attenuation of podocyte injury and inhibition of myofibroblast transformation.
    Journal of Hypertension 09/2014; 32(11). DOI:10.1097/HJH.0000000000000328 · 4.22 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Unlike GLP-1, liraglutide is not cleared by the glomerulus and its pharmacokinetic is not altered in patients with mild renal impairment. The aim of our study was to analyze the effects of liraglutide on renal function in patients with type 2 diabetes. A twelve-month longitudinal prospective post-marketing study was performed. According to eGFR (estimated glomerular filtration rate) calculated with CKD-EPI equation, 84 consecutive patients were divided in Group A (eGFR > 90 ml/min) and Group B (eGFR < 90 ml/min). BMI, glucose, HbA1c, serum creatinine, microalbuminuria, and eGFR were evaluated at baseline and after 12 months of treatment. A reduction in fasting plasma glucose (p < 0.01), HbA1c (p < 0.003), BMI (p < 0.01), and systolic (p < 0.01) and diastolic blood pressure (p < 0.006) was recorded irrespective of eGFR category. Concerning renal function, creatinine levels had a trend to decrease in both groups. eGFR did not change in Group A, while it increased in Group B (p < 0.05) independently from the concomitant changes of other parameters. Moreover, seven out of 41 patients of Group B had increased eGFR levels which reached the normal values (>90 ml/min). At baseline, five patients had pathological microalbuminuria, but at 12 months three of them returned to normal albuminuria (p < 0.006). Total microalbuminuria levels improved in both groups (p < 0.02). According to preliminary data in animals, our study shows that liraglutide is effective in preserving eGFR in diabetic patients, increasing it in those with reduced renal function. This was associated with a decrease of frequency of patients positive to microalbuminuria. Further studies are needed to confirm these data.
    Endocrine 01/2015; DOI:10.1007/s12020-014-0519-0 · 3.53 Impact Factor


Available from
Jun 1, 2014