Liraglutide Improves Renal Endothelial Function in Obese Zucker Rats on a High-Salt Diet

Abstract

Metabolic syndrome is a common risk factor in chronic kidney disease. We investigated whether liraglutide [(LIRA), a glucagonlike peptide-1 receptor (GLP-1R) agonist] treatment improved renal vascular function and renal remodeling in male Zucker rats on a high-salt diet (6% NaCl). Zucker lean (1/1) and obese (fa/fa) rats (8 weeks old) were treated with vehicle or LIRA (0.1 mg/kg per day) for 8 weeks on a high-salt diet. The glomerular filtration rate (GFR) was measured at 0 and 8 weeks using the fluorescein isothiocyanate/sinistrin method in conscious rats. We used X-ray microangiography to measure renal arterial vessel diameter (70-350 mm) and vessel number in vivo in anesthetized rats. Renal protein expression levels of nitrotyrosine, CD-68, endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), transforming growth factor-b1, cyclooxygenase-2, and GLP-1R were assessed by western blotting. Renal gene expressions were determined by real-time polymerase chain reaction. In contrast to vehicletreated rats, fa/fa-LIRA rats improved GFR, nitric oxide (NO)mediated vasodilation in response to acetylcholine and sodium nitroprusside in small arterial vessels (,200 mm diameter). LIRA treatment increased vessel responsivity to NO donors in comparison with vehicle treatment. Increases in the expressions of proinflammatory, profibrotic, and oxidative stress related genes in fa/fa rats relative to 1/1 were unaltered by LIRA, other than a trend toward attenuation of VCAM-1 gene expression. However, LIRA treatment increased protein expressions of eNOS (P 5 0.014) and VEGF (P 5 0.063), while reducing glomerular macrophage infiltration in comparison with vehicle-treated fa/fa rats. Low-dose LIRA treatment improved renal vascular function through amelioration of vascular dysfunction and improved NO-mediated dilation of small intrarenal arteries and arterioles and a reduction in renal inflammation. Some of the findings from this study were part of an oral presentation entitled "Liraglutide treatment improves renal vascular function in Zucker rats as visualized by microangiography" in a symposium at the American Society of Nephrology (Kidney Week) meeting, October 30 to November 5,

Liraglutide treatment improves the coronary microcirculation in insulin resistant Zucker obese rats on a high salt diet

“…In the current study, no significant effect of LIRA on SBP was detected. However, in our hands, LIRA significantly lowered SBP in our previous study with the same rat model [21]. In both studies the LIRA normalized the impairment of renal function to a similar extent.…”

“…These results suggest that LIRA treatment improved the capacity for dilation of micro vessels and hence, improved myocardial perfusion by restoring the balance of tonic ET-1/NO production. Similarly, we showed utilizing the same rat model that improvement in endothelium mediated NO-dependent dilation extends to small arteries and arterioles of the renal circulation [21]. In support of these studies, it has also been established that LIRA increases NO-bioavailability in the vasculature in other disease states including arterial stenosis [33].…”

“…Further, db/db mice fed with high fat diet improved hepatic lipid accumulation by promoting reversal of cholesterol transport [40]. In our model of metabolic syndrome, Vcam-1 mRNA expression showed a strong trend to be reduced by LIRA in the kidney [21] but not in the myocardium [13]. On the other hand, markers of macrophage infiltration (CD68 protein expression and CD+ cell density in sections) suggest that LIRA greatly suppressed macrophage infiltration in both the heart and kidney in our studies.…”

“…Following high-salt diet treatment for 8 weeks, SR contrast microangiography was utilized to measure in vivo coronary arterial vessel internal diameters (50-350 µm) and visualized vessel number in hypertensive insulin resistant +/+ and fa/fa rats (at 16 weeks of age) [21]. Rats were induced with isoflurane (4%) and anesthesia maintained (2%) throughout surgical preparation and the imaging experiment.…”

“…Whether chronic LIRA treatment can prevent the progression of endothelial dysfunction in the coronary circulation and adverse myocardial remodeling associated with metabolic syndrome has not been established. Recently, we showed that chronic LIRA treatment ameliorated the exacerbation of renal dysfunction and renal endothelial dysfunction in the Zucker obese rat model of metabolic syndrome compounded by high Na + diet intake [21]. Since high-salt intake has been shown to potentiate cardiovascular inflammation and oxidative stress we hypothesized that chronic LIRA treatment of young adult Zucker obese rats on high-salt diet also prevents the development of inflammation, oxidative stress, coronary endothelial dysfunction and the pathological remodeling of the myocardium.…”