Background— Chronic kidney disease is a risk factor for cardiovascular disease, increasing all-cause mortality. Some evidence suggests that endothelial dysfunction is present in the early stages of renal insufficiency, but no data exist about its possible role in the progression of renal disease. Thus, we prospectively evaluated the effect of endothelial function on estimated glomerular filtration rate (eGFR) in essential hypertension. Methods and Results— We enrolled 500 never-treated uncomplicated hypertensive subjects with serum creatinine ≤1.5 mg/dL. Endothelial function was measured by strain-gauge plethysmography during intra-arterial infusion of acetylcholine and sodium nitroprusside. eGFR was calculated by use of the Chronic Kidney Disease Epidemiology Collaboration equation. The annual rate of decline of eGFR (ΔeGFR/y) was determined as the difference between the follow-up and baseline eGFR values, with this value divided by the time interval in years. During follow-up (92.3±36.2 months), mean ΔeGFR/y was 1.49±1.65 mL · min ⁻¹ · 1.73 m ^{− 2} , with no significant differences between men and women (1.55±1.72 versus 1.43±1.58 mL · min ⁻¹ · 1.73 m ^{− 2} , respectively; P =0.455). This was correlated with acetylcholine-stimulated forearm blood flow ( r =−0.256, P <0.0001), creatinine ( r =0.141, P =0.001), systolic blood pressure ( r =−0.103, P =0.01), and eGFR ( r =0.092, P =0.020). In multivariable regression analysis, forearm blood flow and systolic blood pressure remained associated with change in eGFR. On average, eGFR changed by 0.37 mL · min ⁻¹ · 1.73 m ^{− 2} for each 100% change in forearm blood flow ( P <0.001) and by 0.1 mL · min ⁻¹ · 1.73 m ^{− 2} for each difference of 10 mm Hg in systolic blood pressure ( P =0.032). Conclusions— We demonstrated that acetylcholine-stimulated vasodilation and systolic blood pressure were associated with eGFR loss after adjustment for other cardiovascular risk factors and antihypertensive treatment.

Interleukin 6 (IL-6) is an independent predictor of type 2 diabetes and cardiovascular disease and is correlated with insulin resistance. Insulin stimulates nitric oxide (NO) production through the IRS-1/PI3-kinase/Akt/eNOS pathway (where IRS-1 is insulin receptor substrate 1, PI3-kinase is phosphatidylinositol 3-kinase, and eNOS is endothelial NO synthase). We asked if IL-6 affects insulin vasodilator action both in human umbilical vein endothelial cells (HUVEC) and in the aortas of C57BL/6J mice and whether this inhibitory effect was caused by increased Ser phosphorylation of IRS-1. We observed that IL-6 increased IRS-1 phosphorylation at Ser³¹² and Ser⁶¹⁶; these effects were paralleled by increased Jun N-terminal protein kinase (JNK) and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and reversed by JNK and ERK1/2 inhibition. In addition, IL-6 treatment resulted in impaired IRS-1 phosphorylation at Tyr⁶¹², a site essential for engaging PI3-kinase. Furthermore, IL-6 treatment reduced insulin-stimulated phosphorylation of eNOS at the stimulatory Ser¹¹⁷⁷ site and impaired insulin-stimulated eNOS dephosphorylation at the inhibitory Thr⁴⁹⁵ site. Insulin-stimulated eNOS activation and NO production were also inhibited by IL-6; these effects were reversed by inhibition of JNK and ERK1/2. Treatment of C57BL/6J mice with IL-6 resulted in impaired insulin-dependent activation of the Akt/eNOS pathway in the aorta as a result of JNK and ERK1/2 activation. Our data suggest that IL-6 impairs the vasodilator effects of insulin that are mediated by the IRS-1/PI3-kinase/Akt/eNOS pathway through activation of JNK and ERK1/2.

OBJECTIVE—Type 2 diabetes and essential hypertension are major risk factors for cardiovascular diseases. Endothelial dysfunction is an early step in the development of atherosclerosis and has been demonstrated in hypertensive and diabetic patients. RESEARCH DESIGN AND METHODS—We designed this study to determine whether forearm endothelial dysfunction is an independent predictor of type 2 diabetes in patients with essential hypertension. We enrolled 400 white never-treated hypertensive outpatients, free of type 2 diabetes at the time of the first evaluation. Endothelium-dependent vasodilation was investigated by intra-arterial infusion of acetylcholine. Insulin resistance was estimated by homeostasis model assessment. RESULTS—During the follow-up (4.5 ± 1.6 years), 44 patients developed type 2 diabetes. The event rate was 2.4 events/100 patient-years. In a multivariate Cox regression analysis, the peak percentage increase in acetylcholine-stimulated forearm blood flow (hazard ratio [HR] 0.77 [95% CI 0.61–0.99]; P = 0.04) and C-reactive protein (1.16 [1.03–1.32]; P = 0.01) resulted in the only independent predictors of type 2 diabetes. CONCLUSIONS—An impaired vasodilatory response to acetylcholine predicts development of type 2 diabetes in patients with essential hypertension. Present data also extend recent findings regarding a possible inflammatory pathogenesis of type 2 diabetes and suggest a new approach in treatment of essential hypertension.

High levels of uric acid (UA) are associated with type-2 diabetes and cardiovascular disease. Recent pieces of evidence attributed to UA a causative role in the appearance of diabetes and vascular damage. However, the molecular mechanisms by which UA induces these alterations have not been completely elucidated so far. Among the mechanisms underlying insulin resistance, it was reported the role of a transmembrane glycoprotein, named either ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) or plasma cell antigen 1, which is able to inhibit the function of insulin receptor (I_R) and it is overexpressed in insulin-resistant subjects. In keeping with this, we stimulated human umbilical vein endothelial cells (HUVECs) with insulin and UA to investigate the effects of UA on insulin signaling pathway, testing the hypothesis that UA can interfere with insulin signaling by the activation of ENPP1. Cultures of HUVECs were stimulated with insulin, UA and the urate transporter SLC22A12 (URAT1) inhibitor probenecid. Akt and endothelial nitric oxide synthase (eNOS) phosphorylation levels were investigated by immunoblotting. ENPP1 binding to I_R and its tyrosine phosphorylation levels were tested by immunoprecipitation and immunoblotting. UA inhibited insulin-induced Akt/eNOS axis. Moreover, UA induced ENPP1 binding to I_R that resulted in an impairment of insulin signaling cascade. Probenecid reverted UA effects, suggesting that UA intracellular uptake is required for its action. In endothelial cells, UA directly interferes with insulin signaling pathway at receptor level, through ENPP1 recruitment. This evidence suggests a new molecular model of UA-induced insulin resistance and vascular damage.