Cerebrovascular Dysfunction in Zucker Obese Rats Is Mediated by Oxidative Stress and Protein Kinase C

Erdös, Benedek; Snipes, James A.; Miller, Allison W.; Busija, David W.

doi:10.2337/diabetes.53.5.1352

Cited by 124 publications

(154 citation statements)

References 52 publications

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“…4 On the other hand, obesity has been shown to increase oxidative stress. 24,25 In this study, 8-OHdG, a recognized oxidative stress marker, decreased significantly after 4 weeks. Although the decreases in body weight, serum creatinine and urinary protein did not correlate with the decrease in 8-OHdG, our results suggested that the decrease in oxidative stress might be one of the mechanisms by which weight loss improved renal function and proteinuria in obese subjects with diabetic nephropathy.…”

Section: Formula Diet For Diabetic Nephropathysupporting

confidence: 53%

Effect of weight loss using formula diet on renal function in obese patients with diabetic nephropathy

et al. 2005

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OBJECTIVE:To evaluate the effect and safety of treatment with low-calorie formula diet on renal function and proteinuria in obese patients with diabetic nephropathy. DESIGN: Prospective study on safety and efficacy of a 4-week low-calorie (11-19 kcal/kg/day) normal-protein (0.9-1.2 g/kg/ day) diet partly supplemented with formula diet. SUBJECTS: In all, 22 obese patients with diabetic nephropathy (BMI: 30.475.3 kg/m 2 , HbA1c: 7.171.4%, serum creatinine: 172.4757.5 mmol/l, urinary protein: 3.372.6 g/day). RESULTS: The mean body weight decreased by 6.273.0 kg. The mean systolic blood pressure, creatinine, blood urea nitrogen, urinary protein, and 8-hydroxydeoxyguanosine decreased significantly by 7.5712.7 mmHg, 41.6723.9 mmol/l, 1.5071.61 mmol/l, 1.871.7 g/day, and 3.173.6 ng/mg creatinine, respectively. No patient had increased serum creatinine and urinary protein. Mean creatinine clearance (40.6717.9 to 46.1714.6 ml/s/1.73 m 2 ) and serum albumin showed no significant changes. Dserum creatinine and Durinary protein correlated with Dbody weight (r ¼ 0.62 and 0.49, respectively) and Dvisceral fat area (r ¼ 0.58 and 0.58, respectively), but did not correlate with Dsystolic blood pressure, Dfasting blood glucose and Dsubcutaneous fat area. CONCLUSION: These results suggested that weight reduction using formula diet might improve renal function and proteinuria safely for a short term in obese patients with diabetic nephropathy.

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Section: Formula Diet For Diabetic Nephropathysupporting

confidence: 53%

Effect of weight loss using formula diet on renal function in obese patients with diabetic nephropathy

et al. 2005

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“…Thus, the present study uncovered unique vascular actions of insulin in cerebral arteries of ZO rats that have not been reported in other circulations such as mesenteric (Miller et al, 2002) or coronary (Katakam et al, 2005). It is noted that vasodilation to nitroprusside was unchanged in ZO arteries compared with ZL arteries (Erdos et al, 2004).…”

Section: Insulin Versus Other Vasodilatorssupporting

confidence: 46%

“…Previous data from our laboratory (Erdos et al, 2004(Erdos et al, , 2006 and others (Oltman et al, 2006;Phillips et al, 2005;Stepp, 2006) have shown that ZO rats develop IR with a metabolic profile very similar to the human condition. As reported previously (Erdos et al, 2004(Erdos et al, , 2006, at 10 to 12 weeks of age, ZO rats had significantly greater body weight and exhibited features typical of metabolic syndrome including impaired glucose tolerance, hyperinsulinemia (widely used marker of IR), hypertriglyceridemia, and hypercholesterolemia. Importantly, young ZO rats used in the present study were insulin resistant but glucose levels and blood pressure were not elevated.…”

Section: Zucker Obese Rat Modelmentioning

confidence: 63%

“…We previously observed that NOmediated vasodilation was diminished in ZO arteries despite the evidence of increased eNOS and iNOS expression compared with ZL arteries (Erdos et al, 2004;Katakam et al, 2009b). Moreover, a reduced phosphorylated NOS protein in response to insulin, consistent with reduced NO-mediated vasodilation, was observed in ZO arteries compared with ZL arteries.…”

Section: Role Of Nitric Oxide Synthase Uncouplingmentioning

confidence: 80%

“…However, the significant distinction displayed by insulin in inducing NOS uncoupling in ZO arteries compared with many vasodilators we previously studied (Erdos et al, 2004;Katakam et al, 2005Katakam et al, , 2009b assures the specificity of insulin's action in cerebrovascular IR. Although it has been reported that hyperleptinemia has been associated with increased eNOS expression and uncoupling (Korda et al, 2008); hyperleptinemia has not been shown to directly stimulate NOS uncoupling.…”

Section: Limitationsmentioning

confidence: 91%

See 2 more Smart Citations

Insulin-Induced Generation of Reactive Oxygen Species and Uncoupling of Nitric Oxide Synthase Underlie the Cerebrovascular Insulin Resistance in Obese Rats

Katakam

Snipes

Steed

et al. 2012

J Cereb Blood Flow Metab

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Hyperinsulinemia accompanying insulin resistance (IR) is an independent risk factor for stroke. The objective is to examine the cerebrovascular actions of insulin in Zucker obese (ZO) rats with IR and Zucker lean (ZL) control rats. Diameter measurements of cerebral arteries showed diminished insulin-induced vasodilation in ZO compared with ZL. Endothelial denudation revealed vasoconstriction to insulin that was greater in ZO compared with ZL. Nonspecific inhibition of nitric oxide synthase (NOS) paradoxically improved vasodilation in ZO. Scavenging of reactive oxygen species (ROS), supplementation of tetrahydrobiopterin (BH 4 ) precursor, and inhibition of neuronal NOS or NADPH oxidase or cyclooxygenase (COX) improved insulin-induced vasodilation in ZO. Immunoblot experiments revealed that insulin-induced phosphorylation of Akt, endothelial NOS, and expression of GTP cyclohydrolase-I (GTP-CH) were diminished, but phosphorylation of PKC and ERK was enhanced in ZO arteries. Fluorescence studies showed increased ROS in ZO arteries in response to insulin that was sensitive to NOS inhibition and BH 4 supplementation. Thus, a vicious cycle of abnormal insulin-induced ROS generation instigating NOS uncoupling leading to further ROS production underlies the cerebrovascular IR in ZO rats. In addition, decreased bioavailability and impaired synthesis of BH 4 by GTP-CH induced by insulin promoted NOS uncoupling.

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Nitric Oxide and the Cardiovascular System

Bohlen

2015

Comprehensive Physiology

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Nitric oxide (NO) generated by endothelial cells to relax vascular smooth muscle is one of the most intensely studied molecules in the past 25 years. Much of what is known about NO regulation of NO is based on blockade of its generation and analysis of changes in vascular regulation. This approach has been useful to demonstrate the importance of NO in large scale forms of regulation but provides less information on the nuances of NO regulation. However, there is a growing body of studies on multiple types of in vivo measurement of NO in normal and pathological conditions. This discussion will focus on in vivo studies and how they are reshaping the understanding of NO's role in vascular resistance regulation and the pathologies of hypertension and diabetes mellitus. The role of microelectrode measurements in the measurement of [NO] will be considered because much of the controversy about what NO does and at what concentration depends upon the measurement methodology. For those studies where the technology has been tested and found to be well founded, the concept evolving is that the stresses imposed on the vasculature in the form of flow-mediated stimulation, chemicals within the tissue, and oxygen tension can cause rapid and large changes in the NO concentration to affect vascular regulation. All these functions are compromised in both animal and human forms of hypertension and diabetes mellitus due to altered regulation of endothelial cells and formation of oxidants that both damage endothelial cells and change the regulation of endothelial nitric oxide synthase.

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Cerebrovascular Dysfunction in Zucker Obese Rats Is Mediated by Oxidative Stress and Protein Kinase C

Cited by 124 publications

References 52 publications

Effect of weight loss using formula diet on renal function in obese patients with diabetic nephropathy

Effect of weight loss using formula diet on renal function in obese patients with diabetic nephropathy

Insulin-Induced Generation of Reactive Oxygen Species and Uncoupling of Nitric Oxide Synthase Underlie the Cerebrovascular Insulin Resistance in Obese Rats

Nitric Oxide and the Cardiovascular System

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