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BackgroundExperimental evidence suggests that sedentary time (ST) may contribute to cardiovascular disease by eliciting detrimental hemodynamic changes in the lower limbs. However, little is known about objectively measured ST and lower extremity peripheral artery disease (PAD).MethodsWe included 7,609 Hispanic/Latinos (ages 45-74) from the Hispanic Community Health Study/Study of Latinos. PAD was measured using the ankle brachial index (≤0.9). ST was measured using accelerometry. We used multivariable logistic regression to assess associations of quartiles of ST and PAD, and then used the same logistic models with restricted cubic splines to investigate continuous nonlinear associations of ST and PAD. Models were sequentially adjusted for traditional PAD risk factors, leg pain, and moderate- to vigorous-intensity physical activity (MVPA).ResultsMedian ST was 12.2 h/d, and 5.4% of individuals had PAD. In fully adjusted restricted cubic splines models accounting for traditional PAD risk factors, leg pain, and MVPA, ST had a significant overall (P = .048) and nonlinear (P = .024) association with PAD. A threshold effect was seen such that time spent above median ST was associated with higher odds of PAD. That is, compared to median ST, 1, 2, and 3 hours above median ST were associated with a PAD odds ratio of 1.16 (95% CI = 1.02-1.31), 1.44 (1.06-1.94), and 1.80 (1.11-2.90), respectively.ConclusionsAmong Hispanic/Latino adults, ST was associated with higher odds of PAD, independent of leg pain, MVPA, and traditional PAD risk factors. Notably, we observed a threshold effect such that these associations were only observed at the highest levels of ST.

ObjectiveBecause Hispanic ethnicity in the United States is heterogeneous, the purpose of this study was to determine the epidemiology of peripheral arterial disease (PAD) within U.S. Hispanic/Latino groups defined by national background.MethodsThis analysis included 9648 men and women older than 45 years enrolled in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). The ankle-brachial index (ABI) was computed as the higher of the posterior tibial and dorsalis pedis systolic blood pressures for each leg divided by the higher brachial artery systolic blood pressure. The index ABI was the higher of the two. An ABI ≤0.90 was the criterion for the presence of PAD.ResultsThe mean age was 56 years, and 55% were female. Overall, the prevalence of an ABI ≤0.90 (PAD), 0.90 to 0.99 (borderline), 1.0 to 1.39 (normal), and ≥1.40 (high) was 5.7%, 19.3%, 72.5%, and 2.6%, respectively. After multivariable adjustment for PAD risk factors and compared with Mexicans, Cubans had a nearly threefold higher odds for PAD (odds ratio, 2.9; 95% confidence interval, 1.9-4.4). The odds of PAD for the other Hispanic/Latino groups ranged from 1.2 to 1.8. Although men had a more than threefold higher odds of an ABI ≥1.40 (3.6; 2.0-6.5), the odds did not differ significantly by Hispanic/Latino background.ConclusionsCompared with Mexican Americans, all other Hispanic/Latino background groups have a significantly higher odds of having PAD, with the odds being nearly threefold higher among Cubans.

BackgroundThe prevention and control of hypertension is an essential component for reducing the burden of cardiovascular diseases. Here we describe the prevalence of hypertension in diverse Hispanic/Latino background groups and describe the proportion who are aware of their diagnosis, receiving treatment, and having their hypertension under control.MethodsThe Hispanic Community Health Study/Study of Latinos is a longitudinal cohort study of 16,415 Hispanics/Latinos, aged 18-74 years from 4 US communities (Bronx, NY; Chicago, IL; Miami, FL; and San Diego, CA). At baseline (2008-2011) the study collected extensive measurements and completed questionnaires related to research on cardiovascular diseases. Hypertension was defined as measured blood pressure ≥140/90mm Hg or use of antihypertensive medication.ResultsThe total age-adjusted prevalence of hypertension in this study was 25.5% as compared with 27.4% in non-Hispanic whites in the National Health and Nutrition Examination Survey. Prevalence of hypertension increased with increasing age groups and was highest in Cuban, Puerto Rican, and Dominican background groups. The percent with hypertension who were aware, being treated with medication, or had their hypertension controlled was lower compared with US non-Hispanic whites with hypertension and it was lowest in those without health insurance.ConclusionsThese findings indicate a significant deficit in treatment and control of hypertension among Hispanics/Latinos residing in the United States, particularly those without health insurance. Given the relative ease of identification of hypertension and the availability of low-cost medications, enabling better access to diagnostic and treatment services should reduce the burden of hypertension in Hispanic populations.

Epidemiological studies have established the role of cigarette smoking as a risk factor in the progression of chronic kidney disease, including diabetic nephropathy. We have previously reported that nicotine promotes mesangial cell proliferation and hypertrophy via activation of non-neuronal nicotinic acetylcholine receptors and that nicotine worsens renal injury in a model of acute glomerulonephritis (Jaimes E, Tian RX, Raij L. Am J Physiol Heart Circ Physiol 292: H76-H82, 2007; Jaimes EA, Tian RX, Joshi M, Raij L. Am J Nephrol 29: 319-326, 2009). These studies were designed to test the hypothesis that nicotine worsens renal injury in db/db mice, a well-established model of diabetic nephropathy, and that reactive oxygen species play an important as mediators of these effects. For these studies, nicotine (100 [micro]g/ml) was administered in the drinking water to control and db/db mice for 10 wk. Blood pressure was measured by the tail-cuff method, and urine was collected for proteinuria. At death, kidneys were collected for histology and molecular biology. The administration of nicotine did not result in significant changes in blood pressure or blood glucose and resulted in cotinine levels similar to those found in the plasma of smokers. In diabetic mice, the administration of nicotine significantly increased urinary protein excretion (1-fold), glomerular hypertrophy, and mesangial area (~20%). These changes were accompanied by significant increases in NADPH oxidase 4 (~30%) and increased nitrotyrosine and Akt expression. In vitro, we determined that nicotine has additive effects to high glucose on reactive oxygen species generation and Akt phosphorylation in human mesangial cells. These findings unveil novel mechanisms that may result in the development of novel strategies in the treatment and prevention of diabetic nephropathy in smokers. reactive oxygen species; tobacco doi: 10.1152/ajprenal.00293.2010.

Am J Physiol Renal Physiol 298: F125-F132, 2010. First published October 28, 2009; doi: 10.1152/ajprenal.00248.2009.--Glomerular endothelial cells (GEC) are strategically situated within the capillary loop and adjacent to the glomerular mesangium. GEC serve as targets of metabolic, biochemical, and hemodynamic signals that regulate the glomerular microcirculation. Unequivocally, hyperglycemia, hypertension, and the local renin-angiotensin system partake in the initiation and progression of diabetic nephropathy (DN). Whether free fatty acids (FFA) and reactive oxygen species (ROS) that have been associated with the endothelial dysfunction of diabetic macrovascular disease also contribute to DN is not known. Since endothelial cells from different organs and from different species may display different phenotypes, we employed human GEC to investigate the effect of high glucose (22.5 mmol/l), FFA (800 [micro]mol/l), and angiotensin II (ANG II; [10.sup.-7] mol/l) on the genesis of ROS and their effects on endothelial nitric oxide synthase (eNOS), cyclooxygenase-2 (COX-2), and the synthesis of prostaglandins (PGs). We demonstrated that high glucose but not high FFA increased the expression of a dysfunctional eNOS as well as increased ROS from NADPH oxidase (100%) and likely from uncoupled eNOS. ANG II also induced ROS from NADPH oxidase. High glucose and ANG II upregulated (100%) COX-2 via ROS and significantly increased the synthesis of prostacyclin ([PGI.sub.2]) by 300%. In contrast, FFA did not upregulate COX-2 but increased [PGI.sub.2] (500%). These novel studies are the first in human GEC that characterize the differential role of FFA, hyperglycemia, and ANG II on the genesis of ROS, COX-2, and PGs and their interplay in the early stages of hyperglcyemia. diabetes; prostaglandins; reactive oxygen species; nitric oxide

Insulin activation of the phosphatidylinositol 3-kinase (PI3K) pathway stimulates glucose uptake in peripheral tissues and synthesis of nitric oxide (NO) in the endothelium. Insulin resistance (IR) and hypertension frequently coexist, particularly among individuals with salt-sensitive hypertension. The mechanisms underlying this association are poorly understood. We investigated these mechanisms in a model of salt-sensitive hypertension in which we have previously shown that endothelial dysfunction is mediated by superoxide anion ([O.sup.-.sub.2]) linked to local ANG II. Dahl salt-sensitive rats were fed, for 6 wk, a normal salt diet (NS; 0.5% NaCl), high-salt diet (HS; 4% NaCl), HS plus the ANG II type 1 receptor (A[T.sub.1]R) blocker (ARB) candesartan (10 mg x [kg.sup.-1] x [day.sup.-1]), or HS plus the antioxidant tempol (172 mg/l in drinking water). Hypertensive (mean arterial pressure: 145 [+ or -] 4 vs. 102 [+ or -] 5 mmHg in NS, P < 0.05) rats manifested increased aortic A[T.sub.1]R mRNA (210%) and protein (101%) expression and [O.sub.2] production (104%) and impaired endothelium-dependent relaxation (EDR) to acetylcholine [maximal response ([E.sub.max]): 68 [+ or -] 9 vs. 91 [+ or -] 8% in NS, P < 0.05]. ARB or tempol normalized [O.sup.-.sub.2] and EDR despite that they did not normalize mean arterial pressure, which was reduced only 25%. Hypertensive rats manifested metabolic IR (36% reduction in the glucose infusion rate by insulin clamp), impaired NO-mediated insulin-induced EDR ([E.sub.max] : 12 [+ or -] 5 vs. 32 [+ or -] 4% in NS, P < 0.05), and impaired insulin activation of PI3K/endothelial NO synthase. ARB or tempol improved insulin-mediated EDR, PI3K, Akt/endothelial NO synthase phosphorylation, and metabolic IR (all P < 0.05). This study provides insight into the mechanisms that underlie the association between metabolic and hypertensive cardiovascular diseases and support the notion that [O.sup.-.sub.2] overproduction linked to tissue ANG II interferes with shared insulin signaling pathways in metabolic and cardiovascular tissues. endothelial function; salt sensitivity

Clinical and experimental studies have provided evidence suggesting that statins exert renoprotective effects. To investigate the mechanisms by which statins may exert renoprotection, we utilized the hypertensive Dahl saltsensitive (DS) rat model, which manifests cardiovascular and renal injury linked to increased angiotensin II-dependent activation of NADPH oxidase and decreased nitric oxide (NO) bioavailability. DS rats given high salt diet (4% NaC1) for 10 wk exhibited hypertension [systolic blood pressure (SBP) 200 [+ or -] 8 vs. 150 [+ or -] 2 mmHg in normal salt diet (0.5% NaC1), P < 0.05], glomeruloscterosis, and proteinuria (158%). This was associated with increased renal oxidative stress demonstrated by urinary 8-[F.sub.2[alpha]]-isoprostane excretion and NADPH oxidase activity, increased protein expression of transforming growth factor (TGF)-[beta] (63%) and fibronectin (181%), increased mRNA expression of the proinflammatory molecules monocyte chemoattractant protein-1 (MCP-1) and lectin-like oxidized LDL receptor-1 (LOX-1), as well as downregulation of endothelial NO synthase (eNOS) activity (-44%) and protein expression. Return to normal salt had no effect on SBP or any of the measured parameters. Atorvastatin (30 mg * [kg.sup.-1] * [day.sup.-1]) significantly attenuated proteinuria and glomerulosclerosis and normalized renal oxidative stress, TGF-[beta]1, fibronectin, MCP-1 and LOX-1 expression, and eNOS activity and expression. Atorvastatin-treated rats showed a modest reduction in SBP that remained in the hypertensive range (174 [+ or -] 8 mmHg). Atorvastatin combined with removal of high salt normalized SBP and proteinuria. These findings suggest that statins mitigate hypertensive renal injury by restoring the balance among NO, TGF-[beta]1, and oxidative stress and explain the added renoprotective effects observed in clinical studies using statins in addition to inhibitors of the renin-angiotensin system. end-organ injury; transforming growth factor; hypertension

Salt-sensitive (SS) hypertension is a vascular diathesis characterized by reduced cardiovascular and renal nitric oxide bioavailability and local upregulation of ANG II. We have demonstrated that rats infused with ANG II manifest increased cortical cyclooxygenase (COX)-2 expression and activity via NADPH oxidase-derived reactive oxygen species (ROS). In the present studies we used Dahl salt-sensitive (DS) rats to test the hypothesis that hypertensive SS rats have increased cortical COX-2 upregulation, which is mediated by ANG II and ROS. DS rats were placed on either a normal-salt diet (0.5% NaCl) or a high-salt diet (4% NaCl) for 6 wk and treated with either the ANG II type 1 (A[T.sub.1]) receptor blocker candesartan (Can, 10 mg.[kg.sup.-1].[day.sup.-1]) or the SOD mimetic tempol (1 mmol/1). Hypertensive SS rats had a twofold increase in the cortical expression of COX-2 as assessed by Western blot. These changes in COX-2 expression were accompanied by a 10-fold increase in COX-2 mRNA expression and a 2-fold increase in the urinary excretion of PG[E.sub.2]. Treatment with either the A[T.sub.1] receptor blocker Can or the SOD mimetic tempol did not reduce blood pressure but resulted in significant reductions in the cortical expression of COX-2 and the urinary excretion of PG[E.sub.2]. In conclusion, we have demonstrated that local activation of the renin-angiotensin system, via increased ROS generation, mediates COX-2 upregulation in hypertensive SS rats. These studies unveil novel mechanistic pathways that may play a role in the pathogenesis of hypertensive renal injury. cyclooxygenase-2

Physiological actions of insulin via activation of the phosphatidylinositol 3-kinase/Akt pathway in the endothelium serve to couple regulation of hemodynamic and metabolic homeostasis. Insulin resistance, endothelial dysfunction, and hypertension increase in prevalence with aging. We investigated the metabolic and endothelial actions of insulin in 24- vs. 3-mo Sprague-Dawley rats. With the use of the hyperinsulinemic euglycemic clamp, the rate of glucose infusion necessary to maintain equivalent plasma glucose (5.5 mmol/l) was similar in 24- vs. 3-mo rats, as was fasting glucose (5.2 [+ or -] 0.33 vs. 4.4 [+ or -] 0.37 mmol/l; mean [+ or -] SE) and insulin (0.862 [+ or -] 0.193 vs. 1.307 [+ or -] 0.230 mg/l). Systolic blood pressure was higher in 24-mo rats (133 [+ or -] 5 vs. 110 [+ or -] 4 mmHg; P = 0.005). Endothelial nitric oxide (NO)-dependent relaxation to insulin was impaired in aortas of 24- vs. 3-mo rats (maximal response 8.9 [+ or -] 4.3 vs. 34.9 [+ or -] 3.9%; P = 0.002); [N.sup.G]-nitro-L-arginine methyl ester abolished insulin-mediated relaxation in 3- but not 24-mo rats. Endothelium NO-dependent (acetylcholine) and -independent (sodium nitroprusside) relaxation, as well as NADPH oxidase activity, were similar in 3- and 24-mo rats. Insulin increased aortic serine phosphorylation of Akt in 3-mo rats by 120% over 24-mo rats (P < 0.05) and serine phosphorylation of endothelial NO synthase (eNOS) in 3-mo rats by 380% over 24-mo rats (P < 0.05). Aortic expression of phosphorylated c-Jun NH2-terminal kinase-1 and serine phosphorylated insulin receptor substrate-1, known mediators of metabolic insulin resistance, was similar in 3- and 24-mo rats. Expression of caveolin-1, a regulator of eNOS activity and insulin signaling, was 55% lower in 24- than 3-mo rats (P = 0.002). In summary, impaired vasorelaxation to insulin in aging was independent of metabolic insulin sensitivity and associated with impaired insulin-mediated activation of the Akt/eNOS pathway, but intact activation of the acetylcholine-mediated [Ca.sup.2+]-calmodulin/eNOS pathway. Vascular insulin resistance in aging may add to the increased susceptibility of this population to vascular injury induced by traditional cardiovascular risk factors. endothelium; nitric oxide; cell signaling; metabolic syndrome doi:10.1152/ajpregu.00138.2007

Cigarette smoke (CS) is the most important source of preventable morbidity and mortality in the United States. Recent clinical studies have suggested that, in addition to being a major cardiovascular risk factor, CS promotes the progression of kidney disease. The mechanisms by which CS promotes the progression of chronic kidney disease have not been elucidated. Here we demonstrate for the first time that human mesangial cells (MCs) are endowed with the nicotinic ACh receptors (nAChRs) [alpha]4, [alpha]5, [alpha]7, [beta]2, [beta]3, and [beta]4. Studies performed in other cell types have shown that these nAChRs are ionotropic receptors that function as agonist-regulated [Ca.sup.2+] channels. Nicotine induced MC proliferation in a dose-dependent manner. At [10.sup -7] M, a concentration found in the plasma of active smokers, nicotine induced MC proliferation [control, 1,328 [+ or -] 50 vs. nicotine, 2,761 [+ or -] 90 counts/minute (cpm); P < 0.05] and increased the synthesis of fibronectin (50%), a critical matrix component involved in the progression of chronic kidney disease. We and others have shown that, in response to PKC activation, MC synthesize reactive oxygen species (ROS) via NADPH oxidase. In the current studies we demonstrate that PKC inhibition as well as diphenyleneiodonium and apocynin, two inhibitors of NADPH oxidase, prevented the effects of nicotine on MC proliferation and fibronectin production, hence establishing ROS as second messengers of the actions of nicotine. Furthermore, nicotine increased the production of ROS as assessed by 2',7'-dichlorofluorescein diacetate fluorescence [control, 184.4 [+ or -] 26 vs. nicotine, 281.5 [+ or -] 26 arbitrary fluorescence units (AFU); n = 5 experiments, P < 0.05]. These studies unveil previously unrecognized mechanisms that indict nicotine, a component of CS, as an agent that may accelerate and promote the progression of kidney disease. glomerular mesangium; extracellular matrix; cell proliferation; reactive oxygen species

Nitric oxide production induced by Vibrio cholerae infection was investigated. Ten healthy individuals aged 18-40 years participated in an experiment designed to determine the mechanisms and localization of nitric oxide production in the intestine and the clinical responses to live Vibrio cholerae infection in humans. Results showed that stable metabolite levels of nitric oxide in plasma and urine increased due to extreme cholera infection and symptomatic infection with Vibrio cholerae. Nitric oxide production was induced by cholera toxin in epithelial cells.

Enhanced activity of endgenous NO in a diabetic rat model is likely to cause basal hyperfiltration and continuous renal vasodilation expressed at decreased renal perfusion pressures. Renal hemodynamic abnormalities detected in experimental diabetes are due to the abnormal activity of NO. The abnormal response curve of renal blood flow is not influenced by prostaglandin synthesis restriction with indomethacin.

Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. Besides glycemic and blood pressure control, environmental factors such as cigarette smoking (CS) adversely affect the progression of DN. The effects of CS on DN progression have been attributed to combustion-generated molecules without consideration to the role of nicotine (NIC), responsible for the addictive properties of both CS and electronic cigarettes (ECs). Podocytes are essential to preserve the structure and function of the glomerular filtration barrier, and strong evidence indicates that early podocyte loss promotes DN progression. We performed experiments in human podocytes and in a mouse model of diabetes that develops nephropathy resembling human DN. We determined that NIC binding to podocytes in concentrations achieved with CS and ECs activated NADPH oxidase, which sets in motion a dysfunctional molecular network integrated by cyclooxygenase 2, known to induce podocyte injury; downregulation of AMP-activated protein kinase, important for maintaining cellular energy stores and antioxidation; and upregulation of CD36, which increased lipid uptake and promoted apoptosis. In diabetic mice, NIC increased proteinuria, a recognized marker of chronic kidney disease progression, accompanied by reduced glomerular podocyte synaptopodin, a crucial stabilizer of the podocyte cytoskeleton, and increased fibronectin expression. This novel study critically implicates NIC itself as a contributor to DN progression in CS and EC users. NEW & NOTEWORTHY In this study, we demonstrate that nicotine increases the production of reactive oxygen species, increases cyclooxygenase-2 expression, and upregulates Cd36 while inducing downregulation of AMP-activated protein kinase. In vivo nicotine increases proteinuria and fibronectin expression in diabetic mice. This study demonstrates that effects of nicotine on podocytes are responsible, at least in part, for the deleterious effects of smoking in the progression of chronic kidney disease, including diabetic nephropathy. [ABSTRACT FROM AUTHOR]