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Biomedical subjects

James R Sowers

Publications and source records attributed to James R Sowers.

At least 19 recordsLinked to original sources
PubMed2007

Albumin activation of NAD(P)H oxidase activity is mediated via Rac1 in proximal tubule cells.

BACKGROUND: Rac1 is a Rho-family small GTP-ase, when activated is pivotal in NAD(P)H oxidase (NOX) activation and generation of reactive oxygen species (ROS). Evidence links Rac1 activation to receptor-mediated albumin endocytosis in the proximal tubule cell (PTC). Thus in states of albumin overload, Rac1 activation could lead to NOX activation and ROS formation in the PTC. Furthermore, accumulating evidence supports that HMG-CoA reductase inhibition may reduce oxidative stress and albuminuria. METHODS: To investigate the role of HMG-CoA reductase inhibition of Rac1 and oxidative stress we used the opossum kidney PTC. ROS generation in the PTC was confirmed using oxidative fluorescent dihydroethidium staining. RESULTS: We observed time-dependent increases in NOX activity with bovine serum albumin (albumin) stimulation (500 microg/dl, maximum at 20 min, p < 0.05) that was inhibited in a concentration-dependent manner with the HMG-CoA reductase inhibitor rosuvastatin (1 microM, p < 0.05). Additionally, the Rac1 inhibitor NSC23766 (100 ng/ml) attenuated albumin activation of NOX. Western blot analysis confirmed Rac1 translocation to plasma membrane in the PTC following albumin stimulation and subsequent inhibition by rosuvastatin and NSC23766. CONCLUSIONS: These data demonstrate that albumin-mediated increases in NOX activity and ROS in PTC are reversed by inhibition of Rac1 signaling with the use of rosuvastatin.

Albumins↗
PubMed2007

Diabetes and arterial stiffening.

Type 2 diabetes (DM-2) has become a major global health problem that has been fueled mainly by increasing obesity and aging of the population. Most studies show that arterial stiffening occurs across all age groups in both type 1 diabetes and DM-2, and among those with impaired fasting glucose, impaired glucose tolerance, and the metabolic syndrome. Arterial stiffening in DM-2 results, in part, from the clustering of hyperglycemia, dyslipidemia and hypertension, all of which may promote insulin resistance, oxidative stress, endothelial dysfunction, and the formation of pro-inflammatory cytokines and advanced glycosylation end-products. Likewise, aging may increase arterial stiffening by altering the proportions of elastin and collagen in the aorta. The consequences of arterial stiffening are increased pulse pressure, hypertension, and a greater risk of cardiovascular disease. Treatment strategies to reduce or prevent arterial stiffening include pharmacologic agents that block the renin-angiotensin-aldosterone system, relax vascular smooth muscle, enhance release of nitric oxide from endothelial cells, and break glycosylation end-product cross-links, and fish oil supplementation.

Animals↗
PubMed2006

Hyponatremia, arginine vasopressin dysregulation, and vasopressin receptor antagonism.

Hyponatremia is often associated with arginine vasopressin (AVP) dysregulation that is regulated by the hypothalamo-neurohypophyseal tract in response to changes in plasma osmolality, commonly in patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Potentially lethal complications of hyponatremia most frequently involve the central nervous system and include anorexia, fatigue, lethargy, delirium, seizures, hypothermia and coma, and require prompt treatment. Chronic hyponatremia also complicates patient care and is associated with increased morbidity and mortality, particularly among patients with congestive heart failure. Conventional treatments for hyponatremia (e.g. fluid restriction, diuretic treatment, and sodium replacement) may not be effective in all patients and can lead to significant adverse events. Preclinical and clinical trial results have shown that AVP receptor antagonism is a promising approach to the treatment of hyponatremia that directly addresses the effects of increased AVP and consequent decreased aquaresis, the electrolyte-sparing excretion of free water. Agents that antagonize V(2) receptors promote aquaresis and can lead to increased serum sodium. Dual-receptor antagonism, in which both V(2) and V(1A) receptors are blocked, may provide additional benefits in patients with hyponatremia.

Aged↗
PubMed2006

Proximal tubule microvilli remodeling and albuminuria in the Ren2 transgenic rat.

TG(mRen2)27 (Ren2) transgenic rats overexpress the mouse renin gene, with subsequent elevated tissue ANG II, hypertension, and nephropathy. The proximal tubule cell (PTC) is responsible for the reabsorption of 5-8 g of glomerular filtered albumin each day. Excess filtered albumin may contribute to PTC damage and tubulointerstitial disease. This investigation examined the role of ANG II-induced oxidative stress in PTC structural remodeling: whether such changes could be modified with in vivo treatment with ANG type 1 receptor (AT(1)R) blockade (valsartan) or SOD/catalase mimetic (tempol). Male Ren2 (6-7 wk old) and age-matched Sprague-Dawley rats were treated with valsartan (30 mg/kg), tempol (1 mmol/l), or placebo for 3 wk. Systolic blood pressure, albuminuria, N-acetyl-beta-D-glucosaminidase, and kidney tissue malondialdehyde (MDA) were measured, and x60,000 transmission electron microscopy images were used to assess PTC microvilli structure. There were significant differences in systolic blood pressure, albuminuria, lipid peroxidation (MDA and nitrotyrosine staining), and PTC structure in Ren2 vs. Sprague-Dawley rats (each P < 0.05). Increased mean diameter of PTC microvilli in the placebo-treated Ren2 rats (P < 0.05) correlated strongly with albuminuria (r(2) = 0.83) and moderately with MDA (r(2) = 0.49), and there was an increase in the ratio of abnormal forms of microvilli in placebo-treated Ren2 rats compared with Sprague-Dawley control rats (P < 0.05). AT(1)R blockade, but not tempol treatment, abrogated albuminuria and N-acetyl-beta-d-glucosaminidase; both therapies corrected abnormalities in oxidative stress and PTC microvilli remodeling. These data indicate that PTC structural damage in the Ren2 rat is related to the oxidative stress response to ANG II and/or albuminuria.

Acetylglucosaminidase↗
PubMed2006

Angiotensin II-induced NADPH oxidase activation impairs insulin signaling in skeletal muscle cells.

The renin-angiotensin system (RAS) and reactive oxygen species (ROS) have been implicated in the development of insulin resistance and its related complications. There is also evidence that angiotensin II (Ang II)-induced generation of ROS contributes to the development of insulin resistance in skeletal muscle, although the precise mechanisms remain unknown. In the present study, we found that Ang II markedly enhanced NADPH oxidase activity and consequent ROS generation in L6 myotubes. These effects were blocked by the angiotensin II type 1 receptor blocker losartan, and by the NADPH oxidase inhibitor apocynin. Ang II also promoted the translocation of NADPH oxidase cytosolic subunits p47phox and p67phox to the plasma membrane within 15 min. Furthermore, Ang II abolished insulin-induced tyrosine phosphorylation of insulin receptor substrate 1 (IRS1), activation of protein kinase B (Akt), and glucose transporter-4 (GLUT4) translocation to the plasma membrane, which was reversed by pretreating myotubes with losartan or apocynin. Finally, small interfering RNA (siRNA)-specific gene silencing targeted specifically against p47phox (p47siRNA), in both L6 and primary myotubes, reduced the cognate protein expression, decreased NADPH oxidase activity, restored Ang II-impaired IRS1 and Akt activation as well as GLUT4 translocation by insulin. These results suggest a pivotal role for NADPH oxidase activation and ROS generation in Ang II-induced inhibition of insulin signaling in skeletal muscle cells.

Angiotensin II↗
PubMed2006

Oxidative stress and glomerular filtration barrier injury: role of the renin-angiotensin system in the Ren2 transgenic rat.

TG(mRen2)27 (Ren2) transgenic rats overexpress the mouse renin gene, manifest hypertension, and exhibit increased tissue ANG II levels and oxidative stress. Evidence indicates that elevated tissue ANG II contributes to oxidative stress, increases in glomerular macromolecular permeability, and consequent albuminuria. Furthermore, angiotensin type 1 receptor (AT1R) blockers reduce albuminuria and slow progression of renal disease. However, it is not known whether improvements in glomerular filtration barrier integrity and albuminuria during treatment are related to reductions in oxidative stress and/or kidney renin-angiotensin system (RAS) activity. To investigate the renal protective effects of AT1R blockade, we treated young (6-7 wk old) male Ren2 rats with valsartan (Ren2-V; 30 mg/kg) for 3 wk and measured urine albumin, kidney malondialdehyde (MDA), RAS component mRNAs, and NADPH oxidase subunits (gp91(phox) and Rac1) compared with age-matched untreated Ren2 and Sprague-Dawley (S-D) rats. Basement membrane thickness, slit pore diameter and number, and foot process base width were measured by transmission electron microscopy (TEM). Results indicate that AT1R blockade lowered systolic blood pressure (30%), albuminuria (91%), and kidney MDA (80%) in Ren2-V compared with untreated Ren2 rats. Increased slit pore number and diameter and reductions in basement membrane thickness and podocyte foot process base width were strongly associated with albuminuria and significantly improved following AT1R blockade. AT1R blockade was also associated with increased angiotensin-converting enzyme-2 and neprilysin expression, demonstrating a beneficial shift in balance of renal RAS. Thus reductions in blood pressure, albuminuria, and tissue oxidative stress with AT1R blockade were associated with improved indexes of glomerular filtration barrier integrity and renal RAS in Ren2 rats.

Albuminuria↗
PubMed2006

Cardiometabolic syndrome and chronic kidney disease.

Chronic kidney disease (CKD) is increasingly recognized as a major risk factor for end-stage renal disease (ESRD), cardiovascular (CV) disease, and CV-related premature death. More than 8 million people in the United States have CKD; therefore, preventive stratiegies should be directed at identifying risk factors for this condition. There is growing evidence implicating the cardiometabolic syndrome, a clustering of CV risk factors that include obesity, insulin resistance, compensatory hyperinsulinemia, dysglycemia, atherogenic dyslipidemia, and hypertension. Factors mediating this relationship include increased glomerular filtration, increased vascular permeability, oxidative and endoplasmic reticulum stress, activation of the renin-angiotensin system, and inappropriate secretion of growth factors. The consequences are microalbuminuria, a marker of inflammation and endothelial dysfunction, renal vascular proliferation, extracellular matrix expansion, and CKD. Prevention of CKD should be directed at controlling all components of the cardiometabolic syndrome, with the ultimate goal of reducing the burden imposed by ESRD.

Albuminuria↗
PubMed2006

Anemia and cardiovascular disease in diabetic nephropathy.

Cardiovascular disease (CVD) is the major cause of morbidity and mortality in people with diabetes and in those with chronic kidney disease (CKD). Diabetes, occurring in epidemic proportions in the United States and worldwide, is also the leading cause of CKD and kidney failure. Identification of modifiable risk factors for CVD in patients with diabetes and CKD is thus of paramount importance. Anemia is increasingly recognized as a potential CVD risk factor in patients with diabetic nephropathy, in whom it is generally more severe and occurs at an earlier stage of CKD. In this review, we discuss the epidemiologic evidence, pathophysiologic mechanisms, and the current research findings, highlighting the role of anemia as a potential modifiable risk factor for CVD in patients with diabetic nephropathy, a particularly vulnerable population for CVD.

Anemia↗
PubMed2006

Adrenocortical hypertension.

Primary aldosteronism, congenital adrenal hyperplasia, Cushing's syndrome, glucocorticoid-remediable aldosteronism, and corticotropin-dependent forms of adrenal pathology can cause hypertension by excessive production of adrenocortical hormones. Although traditional biochemical assays continue to be used, genetic testing has simplified the diagnosis of glucocorticoid-remediable aldosteronism. Also new interventional radiologic approaches for the diagnosis and treatment of corticotropin-dependent forms of Cushing's syndrome are available. Medical and surgical approaches, however, still remain viable options for treatment.

Journal Article↗
PubMed2006

Obesity, cardiometabolic syndrome, and chronic kidney disease: the weight of the evidence.

The epidemic of obesity experienced in both industrialized and nonindustrialized countries largely accounts for the increase in the prevalence of the cardiometabolic syndrome (CMS). Obesity and the CMS significantly increase the risk for cardiovascular disease (CVD) and chronic kidney disease (CKD). Multiple abnormalities that can lead to kidney injury have been identified in overweight and obese people, including insulin resistance, compensatory hyperinsulinemia, inappropriate activation of the renin-angiotensin-aldosterone system and increased oxidative stress, endoplasmic reticulum stress, coagulability, and impaired fibrinolysis. The combined effects of these conditions induce in the kidneys impaired pressure natriuresis, glomerular hypertension, endothelial dysfunction, and vasoconstriction, as well as matrix proliferation and expansion. Among the consequences are microalbuminuria, now known to be a surrogate of diffuse endothelial dysfunction as well as a predictor of CVD, and CKD. Diet and regular physical activity are the cornerstones of weight management, and they add to currently available pharmacologic agents and bariatric surgery. The understanding of the pathophysiology of obesity/CMS helps to explain the benefits of agents that improve insulin sensitivity, control inflammation, and block the renin-angiotensin-aldosterone system. The increasing prevalence of obesity and CMS contribute to the growing frequency of CKD and demands the development of multifactorial strategies directed at identifying people at risk, as well as preventing excessive weight gain and its deleterious consequences.

Albuminuria↗
PubMed2006

The metabolic syndrome: role of skeletal muscle metabolism.

Skeletal muscle constitutes the largest insulin-sensitive tissue in the body and is the primary site for insulin-stimulated glucose utilization. Skeletal muscle resistance to insulin is fundamental to the metabolic dysregulation associated with obesity and physical inactivity, and contributes to the development of the metabolic syndrome (MS). The inability to efficiently take up and store fuel, and to transition from fat to glucose as the primary source of fuel during times of caloric abundance (high insulin) or scarcity (low insulin) has been termed metabolic inflexibility which contributes to a whole body metabolic dysregulation and cardiovascular risk. Potential mechanisms contributing to reduced insulin signaling and action in skeletal muscle includes adipose tissue expansion and increased inflammatory adipokines, increased renin-angiotensin-aldosterone system (RAAS) activity, decreases in muscle mitochondrial oxidative capacity, increased intramuscular lipid accumulation, and increased reactive oxygen species. Future research is focused upon understanding these and other potential mechanisms in order to identify therapeutic targets for reducing MS risk. Strategies will include adequate physical activity and maintaining a healthy weight, but may also require specific pharmacologic interventions.

Angiotensin II↗
PubMed2006

Hypertension--a treatable component of the cardiometabolic syndrome: challenges for the primary care physician.

Patients with the cardiometabolic syndrome (CMS) have an adverse cardiovascular risk factor profile, placing them at increased risk of stroke, coronary artery disease, chronic kidney disease, and type 2 diabetes mellitus. Although no specific treatments for CMS are available per se, prompt recognition and treatment of the individual components of the condition can prevent or delay the development of comorbidities. Primary care physicians are ideally positioned to identify patients with CMS and implement early intervention strategies. Hypertension contributes to many complications of CMS, and rigorous blood pressure control will help to delay or prevent end-organ vascular damage. Achieving blood pressure control to current guideline standards should be eagerly sought in the majority of patients through a combination of lifestyle modifications and appropriate pharmacologic therapy. Antihypertensive drug choice should be personalized, taking into account the CMS determinants present and any compelling indications for specific agents. As an initial approach, a thiazide diuretic is suitable for most cases of uncomplicated hypertension, although many patients will require additional antihypertensives from other classes to achieve their blood pressure goal. It is predicted that, due to the increase in unhealthy lifestyles, the prevalence of CMS will rise in the coming years. Therefore, by meeting the challenge of attaining and maintaining blood pressure control in patients with CMS, primary care physicians have the unique opportunity to markedly improve the health of the nation.

Albuminuria↗
PubMed2006

Antihypertensive efficacy of Irbesartan/HCTZ in men and women with the metabolic syndrome and type 2 diabetes.

This subgroup analysis of the Irbesartan/Hydrochlorothiazide (HCTZ) Blood Pressure Reductions in Diverse Patient Populations (INCLUSIVE) trial evaluated the efficacy and safety of irbesartan/HCTZ fixed combinations in adults with uncontrolled systolic blood pressure (SBP) (140-159 mm Hg; 130-159 mm Hg for type 2 diabetes mellitus [T2DM]) after >or=4 weeks of antihypertensive monotherapy. Treatment was sequential: placebo (4-5 weeks), HCTZ 12.5 mg (2 weeks), irbesartan/HCTZ 150/12.5 mg (8 weeks), and irbesartan/HCTZ 300/25 mg (8 weeks). In the intent-to-treat analysis, mean change from baseline (end of placebo phase) off all previous therapy to Week 18 (study end) in T2DM patients (n=227) was -18.2+/-14.1 mm Hg for SBP (primary end point; p<0.001) and -8.7+/-8.2 mm Hg for diastolic blood pressure (p<0.001). Mean SBP/diastolic blood pressure changes in patients with the metabolic syndrome (n=345) were -21.0+/-14.3/-10.4+/-8.5 mm Hg (p<0.001). Overall, 56% (95% confidence interval, 49%-62%) of T2DM and 73% (95% confidence interval, 68%-77%) of metabolic syndrome patients achieved SBP goal (<140 mm Hg; <130 mm Hg for T2DM). Goal attainment rates were significantly higher among women with the metabolic syndrome than men. Treatments appeared to be well tolerated. Irbesartan/HCTZ fixed combinations achieved SBP goals in over half of the T2DM patients and nearly three quarters of patients with the metabolic syndrome, with SBP uncontrolled on antihypertensive monotherapy.

Adult↗
PubMed2006

Effect of antihypertensive agents on the development of type 2 diabetes mellitus.

People with hypertension have a high prevalence of insulin resistance and are at relatively high risk of developing type 2 diabetes mellitus. It is becoming increasingly evident that antihypertensive agents have disparate metabolic effects. For example, recent clinical trials indicate that agents that interrupt the renin-angiotensin axis reduce the risk of developing diabetes compared with other classes of antihypertensive agents. Blockade of the effects of angiotensin II might improve blood flow to insulin-sensitive tissues. Furthermore, interruption of the renin-angiotensin system might provide metabolic benefit through such mechanisms as reduced oxidative stress and restored nitric oxide production, which could lead to improved insulin signaling. Alternatively, collective trials suggest that both diuretics and beta-blockers accelerate the appearance of new-onset type 2 diabetes mellitus in patients with hypertension. Therefore, the risk of new-onset diabetes-associated cardiovascular risks should be factored into future treatment recommendations for patients who require antihypertensive therapy. This will become even more important as the number of insulin-resistant patients with hypertension increases in parallel with the steady growth in the number of sedentary, obese, and aged persons in our population.

Antihypertensive Agents↗
PubMed2006

Irbesartan/HCTZ fixed combinations in patients of different racial/ethnic groups with uncontrolled systolic blood pressure on monotherapy.

The IrbesartaN/hydroChlorothiazide (HCTZ) bLood pressUre reductionS In diVErse patient populations (INCLUSIVE) trial was a multicenter, prospective, open-label, single-arm study evaluating the efficacy and safety of irbesartan/HCTZ fixed combinations in patients > or = 18 years old with uncontrolled systolic blood pressure (SBP, 140-159 mmHg; 130-159 mmHg for type-2 diabetes mellitus patients) after > or = 4 weeks of antihypertensive monotherapy. This analysis focused on different racial/ethnic subgroups. Treatment was sequential: placebo (4-5 weeks), HCTZ 12.5 mg (two weeks), irbesartan/HCTZ 150/12.5 mg (eight weeks) and irbesartan/HCTZ 300/25 mg (eight weeks). Overall, 515 Caucasians, 191 African Americans and 119 Hispanics/Latinos completing placebo treatment were enrolled. Mean SBP changes from baseline (placebo treatment end) to week 18 were -21.5 +/- 13.8 mmHg for Caucasians, -20.7 +/- 16.5 mmHg for African Americans and -22.9 +/- 13.2 mmHg for Hispanics/Latinos, respectively (p<0.001 for each). Mean diastolic BP (DBP) changes were statistically significant (p<0.001) and similar among racial/ethnic subgroups. By week 18, 70% (95% CI, 66%, 74%) of Caucasian, 66% (95% CI, 59%, 74%) of African-American and 65% (95% CI, 57%, 74%) of Hispanic/Latino patients achieved dual SBP/DBP goal. Treatments appeared to be well tolerated. In conclusion, irbesartan/HCTZ treatment provided SBP/DBP goal attainment in approximately two-thirds of Caucasian, African-American and Hispanic/Latino patients with SBP uncontrolled on antihypertensive monotherapy.

Antihypertensive Agents↗
PubMed2005

The central role of vascular extracellular matrix and basement membrane remodeling in metabolic syndrome and type 2 diabetes: the matrix preloaded.

The vascular endothelial basement membrane and extra cellular matrix is a compilation of different macromolecules organized by physical entanglements, opposing ionic charges, chemical covalent bonding, and cross-linking into a biomechanically active polymer. These matrices provide a gel-like form and scaffolding structure with regional tensile strength provided by collagens, elasticity by elastins, adhesiveness by structural glycoproteins, compressibility by proteoglycans--hyaluronans, and communicability by a family of integrins, which exchanges information between cells and between cells and the extracellular matrix of vascular tissues. Each component of the extracellular matrix and specifically the capillary basement membrane possesses unique structural properties and interactions with one another, which determine the separate and combined roles in the multiple diabetic complications or diabetic opathies. Metabolic syndrome, prediabetes, type 2 diabetes mellitus, and their parallel companion (atheroscleropathy) are associated with multiple metabolic toxicities and chronic injurious stimuli. The adaptable quality of a matrix or form genetically preloaded with the necessary information to communicate and respond to an ever-changing environment, which supports the interstitium, capillary and arterial vessel wall is individually examined.

Basement Membrane↗