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Whaley-Connell A.T.,Harry uman Va Medical Center | Habibi J.,Harry uman Va Medical Center | Nistala R.,Harry uman Va Medical Center | Demarco V.G.,Harry uman Va Medical Center | And 7 more authors.
American Journal of Nephrology | Year: 2012

Background/Aims: The mammalian target of rapamycin (mTOR) is a serine kinase that regulates phosphorylation (p) of its target ribosomal S6 kinase (S6K1), whose activation can lead to glomerular and proximal tubular cell (PTC) injury and associated proteinuria. Increased mTOR/S6K1 signaling regulates signaling pathways that target fibrosis through adherens junctions. Recent data indicate aldosterone signaling through the mineralocorticoid receptor (MR) can activate the mTOR pathway. Further, antagonism of the MR has beneficial effects on proteinuria that occur independent of hemodynamics. Methods: Accordingly, hypertensive transgenic TG(mRen2)27 (Ren2) rats, with elevated serum aldosterone and proteinuria, and age-matched Sprague-Dawley rats were treated with either a low dose (1 mg/kg/day) or a conventional dose (30 mg/kg/day) of spironolactone (MR antagonist) or placebo for 3 weeks. Results: Ren2 rats displayed increases in urine levels of the PTC brush border lysosomal enzyme N-acetyl-β- aminoglycosidase (β-NAG) in conjunction with reductions in PTC megalin, the apical membrane adherens protein T-cadherin and basolateral α-(E)-catenin, and fibrosis. In concert with these abnormalities, Ren2 renal cortical tissue also displayed increased Ser2448 (p)/activation of mTOR and Thr389 (p)-S6K1 and increased 3-nitrotyrosine (3-NT) content, a marker for peroxynitrite. Low-dose spironolactone had no effect on blood pressure but decreased proteinuria and β-NAG comparable to a conventional dose of this MR antagonist. Both doses of spironolactone attenuated ultrastructural maladaptive alterations and led to comparable reductions in (p)-mTOR/(p)-S6K1, 3-NT, fibrosis, and increased expression of α-(E)-catenin, T- and N-cadherin. Conclusions: Thereby, MR antagonism improves proximal tubule integrity by targeting mTOR/S6K1 signaling and redox status independent of changes in blood pressure. Copyright © 2011 S. Karger AG, Basel. Source


Young C.N.,Medical Pharmacology and Physiology | Deo S.H.,Medical Pharmacology and Physiology | Chaudhary K.,Harry uman Va Medical Center | Thyfault J.P.,Nutrition and Exercise Physiology | And 3 more authors.
Journal of Physiology | Year: 2010

Recent animal studies indicate that insulin increases arterial baroreflex control of lumbar sympathetic nerve activity; however, the extent to which these findings can be extrapolated to humans is unknown. To begin to address this, muscle sympathetic nerve activity (MSNA) and arterial blood pressure were measured in 19 healthy subjects (27 ± 1 years) before, and for 120 min following, two common methodologies used to evoke sustained increases in plasma insulin: a mixed meal and a hyperinsulinaemic euglycaemic clamp. Weighted linear regression analysis between MSNA and diastolic blood pressure was used to determine the gain (i.e. sensitivity) of arterial baroreflex control of MSNA. Plasma insulin was significantly elevated within 30 min following meal intake (Δ34 ± 6 uIU ml-1; P < 0.05) and remained above baseline for up to 120 min. Similarly, after meal intake, arterial baroreflex-MSNA gain for burst incidence and total MSNA was increased and remained elevated for the duration of the protocol (e.g. burst incidence gain: -3.29 ± 0.54 baseline vs.-5.64 ± 0.67 bursts (100 heart beats)-1 mmHg-1 at 120 min; P < 0.05). During the hyperinsulinaemic euglycaemic clamp, in which insulin was elevated to postprandial concentrations (Δ42 ± 6 μIU ml-1; P < 0.05), while glucose was maintained constant, arterial baroreflex-MSNA gain was similarly enhanced (e.g. burst incidence gain: -2.44 ± 0.29 baseline vs.-4.74 ± 0.71 bursts (100 heart beats)-1 mmHg-1 at 120 min; P < 0.05). Importantly, during time control experiments, with sustained fasting insulin concentrations, the arterial baroreflex-MSNA gain remained unchanged. These findings demonstrate, for the first time in healthy humans, that increases in plasma insulin enhance the gain of arterial baroreflex control of MSNA. © 2010 The Authors. Journal compilation © 2010 The Physiological Society. Source


Sowers J.R.,Diabetes and Metabolism | Sowers J.R.,University of Missouri | Sowers J.R.,Diabetes and Cardiovascular Center | Sowers J.R.,Harry uman Va Medical Center | And 4 more authors.
CardioRenal Medicine | Year: 2011

The presence of a group of interactive maladaptive factors including hypertension, insulin resistance, metabolic dyslipidemia, obesity, microalbuminuria, and/or reduced renal function constitute the cardiorenal metabolic syndrome (CRS). Overweight, obesity, and chronic kidney disease (CKD) have grown to pandemic proportions in industrialized countries during the past decade. The fact that these interactive factors promote heart and renal disease has been documented in large population-based studies. Obesity seems to be the driving force behind the development of heart disease and CKD and therefore the CRS. The relationship between overweight/obesity and kidney disease begins in early childhood and appears to be related to overconsumption of high-fructose corn syrup and insufficient physical activity. Today, 13 million children are obese, and over 70% of these children are likely to become obese adults. Indeed, approximately 30% of male and 34% of female adults in the United States are obese. This lifestyle-related epidemic will be a major societal medical and economic problem that will accentuate the current epidemic of CKD in the United States and other industrialized and emerging industrialized countries. In this article, we will review the potential mechanisms by which obesity and other metabolic abnormalities interact to promote heart and progressive kidney disease. Copyright © 2011 S. Karger AG, Basel. Source


Lishmanov A.,University of Missouri | Senthilkumar A.,Harry uman Va Medical Center | Chockalingam A.,Harry uman Va Medical Center
Congestive Heart Failure | Year: 2010

Tachycardia-induced cardiomyopathy is caused by sustained rapid ventricular rates and is one of the well-known forms of reversible myocardial dysfunction. The diagnosis is usually made retrospectively after marked improvement in systolic function is noted following control of the heart rate. Physicians should be aware that patients with seemingly idiopathic systolic dysfunction may have tachycardia-induced cardiomyopathy and that controlling the heart rate may result in improvement or even complete restoration of systolic function. © 2010 Wiley Periodicals, Inc. Source


Mittal M.K.,University of Missouri | Chockalingam A.,University of Missouri | Chockalingam A.,Harry uman Va Medical Center
American Journal of Therapeutics | Year: 2011

Heart failure (HF) is a leading cause of morbidity and mortality. Appropriate medical therapy using angiotensin converting enzyme inhibitors and beta-blockers improves outcomes in HF, whereas the role of digoxin is still not clearly defined. Digoxin is currently recommended for patients with HF who are symptomatic despite standard therapy and for controlling the ventricular rate in atrial fibrillation. Digoxin is a time-tested drug that accounts for 20 million drug prescriptions annually in the United States. It has favorable hemodynamic effects for patients with HF and atrial tachyarrhythmias. We conducted a systematic literature search for the current indications for digoxin. Despite extensive research and safety data, the literature suggests that digoxin is underused in clinical settings. Citing the literature where available, our review highlights the various clinical settings where digoxin is indicated. Despite difficulties with designing prospective studies in acute HF settings and lack of outcomes data, we believe that digoxin will continue to serve an important role in optimizing care in certain acute and chronic cardiac conditions. © 2011 Lippincott Williams & Wilkins. Source

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