Increased Aldosterone Levels in a Model of Type 2 Diabetes Mellitus

Fredersdorf, Sabine; Endemann, Dierk; Luchner, Andreas; Heitzmann, Dirk; Ulucan, Coskun; Birner, Christoph; Schmid, Peter; Stoelcker, Benjamin; Resch, Markus; Muders, Frank; Riegger, G. A. J.; Weil, Joachim

doi:10.1055/s-2008-1073128

Cited by 30 publications

(26 citation statements)

References 17 publications

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“…In addition, our study demonstrated significant elevation of plasma aldosterone in ZDF rats (supporting a compromised cardiovascular function and cardiac distress), but no further elevation of this hormonal biomarker of HF in response to RGZ treatment of ZDF rats was noted (Fig. 4), Table 1 which is in agreement with a previous report (Fredersdorf et al, 2009). Inflammation is another important cardiovascular risk, which is also known to be associated with MI-induced HF (Kherani et al, 2004).…”

Section: Discussionsupporting

confidence: 82%

Pharmacogenomic, Physiological, and Biochemical Investigations on Safety and Efficacy Biomarkers Associated with the Peroxisome Proliferator-Activated Receptor-γ Activator Rosiglitazone in Rodents: A Translational Medicine Investigation

Wang

Liu²,

Zhan³

et al. 2010

J Pharmacol Exp Ther

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Peroxisome proliferator-activated receptor (PPAR)-␥ modulators, a class of antidiabetic drugs, have been associated with cardiovascular risks in type 2 diabetes in humans. The objective of this study was to explore possible cardiovascular risk biomarkers associated with PPAR-␥ in rodents that could provide an alert for risk to humans. Normal, myocardial infarction-induced heart failure (HF) or Zucker diabetic fatty (ZDF) rats were used. Rats (n ϭ 5-6) were treated with either vehicle or rosiglitazone (RGZ; 3 or 45 mg/kg/day p.o.) for 4 weeks. Biomarkers for potential cardiovascular risks were assessed, including 1) ultrasound for cardiac structure and function; 2) neuroendocrine and hormonal plasma biomarkers of cardiovascular risk; 3) pharmacogenomic profiling of cardiac and renal tissue by targeted tissue low-density gene array representing ion channels and transporters, and components of the renin-angiotensin-aldosterone system; and 4) immunohistochemistry for cardiac fibrosis, hypertrophy, and inflammation (macrophages and tumor necrosis factor-␣). HF was confirmed by increase in cardiac brain natriuretic peptide expression (p Ͻ 0.01) and echocardiography. Adequate exposure of RGZ was confirmed by pharmacokinetics (plasma drug levels) and the pharmacodynamic biomarker adiponectin. In normal or HF rats, RGZ had no negative effects on any of the biomarkers investigated. Similarly, RGZ had no significant effects on gene expression except for the increase in interleukin-6 mRNA expression in the heart and decrease in epithelial sodium channel ␤ in the kidney. In contrast, echocardiography showed improved cardiac structure and function after RGZ in ZDF rats. Taken together, this study suggests a limited predictive power of these preclinical models in respect to observed clinical adverse effects associated with RGZ.

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Section: Discussionsupporting

confidence: 82%

Pharmacogenomic, Physiological, and Biochemical Investigations on Safety and Efficacy Biomarkers Associated with the Peroxisome Proliferator-Activated Receptor-γ Activator Rosiglitazone in Rodents: A Translational Medicine Investigation

Wang

Liu²,

Zhan³

et al. 2010

J Pharmacol Exp Ther

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“…An association has been demonstrated in animal models between elevated aldosterone, type 2 diabetes, and the development of diabetic nephropathy (31). This finding in combination with our previous work showing a significant prevalence of microalbuminuria in adolescents with type 2 diabetes (12) suggests that aldosterone receptor blockade may have an important role in the treatment of hypertension in this patient population.…”

Section: Discussionsupporting

confidence: 75%

Relationships Between Renin, Aldosterone, and 24-Hour Ambulatory Blood Pressure in Obese Adolescents

Shatat

Flynn

2011

Pediatr Res

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Renin-angiotensin system (RAS) activation and abnormalities of ambulatory blood pressure (ABP) are present in obesity, but relationships between components of the RAS and ABP have not been defined in the young. Anthropometric measurements and 24-h ABP were obtained on 30 obese adolescents with and without type 2 diabetes mellitus. Plasma renin activity (PRA), aldosterone, and other cardiovascular risk factors were measured. Median PRA levels were 2.5 [interquartile range (IQR), 1.7-4.1] ng/mL/h and were higher in the diabetic subjects compared with the nondiabetics. Females had significantly higher PRA than males 3.2 (IQR, 2-4.8) versus 1.8 (IQR, 1.1-2.9) ng/mL/h (p ϭ 0.04) and were more obese. BMI Z score and PRA were significantly correlated (rho ϭ 0.46, p Ͻ 0.001). PRA inversely correlated with 24-h systolic ABP (rho ϭ Ϫ0.46, p ϭ 0.02) and strongly with 24-h pulse pressure (rho ϭ Ϫ0.61, p ϭ 0.001). Aldosterone levels were also correlated with 24-h pulse pressure (rho ϭ Ϫ0.46, p ϭ 0.02). In multivariate models, lower PRA was independently associated with 24-h systolic blood pressure. In this study, PRA was positively correlated with BMI, but the relationships between components of the RAS and ABP were inverse. Further studies are needed to define the pathophysiologic relationship between RAS components and blood pressure regulation in obese youth. T he renin-angiotensin system (RAS) plays a central role in blood pressure (BP) regulation and fluid-electrolyte homeostasis, and its dysregulation contributes to the development of hypertension (1). Activation of the RAS in adipose tissue may represent an important link between obesity and hypertension. Studies have demonstrated that rat and human adipose tissue possess all of the components necessary for production of angiotensin II (Ang II), including angiotensinogen (2), renin-like activity (3), Ang-converting enzyme, and Ang type 1 receptor (4,5). Adipose-derived angiotensinogen is also released into the circulation where it serves as substrate for conversion to bioactive Ang II, contributes to plasma Ang II levels, and increases BP (6).Other metabolically active products of adipose tissue include adipokines. We have previously shown that adiponectin (an anti-inflammatory, anti-atherosclerotic adipokine) levels are inversely related to ambulatory blood pressure (ABP) (7), which is itself abnormal in obesity.Whether components of the RAS have similar relationships to ABP in obese youth is unknown. Our objective in this study was to examine the relationships between 24-h BP measurements and plasma renin activity (PRA) and aldosterone levels in obese adolescents. MATERIALS AND METHODSSetting and study design. Patients who fulfilled the following criteria were recruited from the Pediatric Diabetes and Pediatric Nephrology Clinics at the Children's Hospital at Montefiore in the Bronx, NY: age 10 to 21 y, obesity defined as BMI Ͼ95th percentile for age and gender (8), a diagnosis within the past 3 y of type 2 diabetes mellitus (T2DM) according to the standar...

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“…In adrenal tissue, Fredersdorf et al demonstrated increased levels of aldosterone in diabetic animals. 47 These results could be related to augmented activity of ACE both in kidney and adrenal tissue, which could enhance the amount of AII with stimulation of the production of aldosterone. However, it is important to emphasize that the size of the gland represents a limiting factor for assessing the concentration of angiotensin peptides present in the tissue.…”

Section: Figurementioning

confidence: 99%

Renin-angiotensin system may trigger kidney damage in NOD mice

Colucci

Arita

Cunha

et al. 2010

J Renin Angiotensin Aldosterone Syst

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Diabetic nephropathy is a complication of diabetes and one of the main causes of end-stage renal disease. A possible causal link between renin-angiotensin aldosterone system (RAAS) and diabetes is widely recognized but the mechanisms by which the RAAS may lead to this complication remains unclear. The aim of this study was to evaluate angiotensin-I converting enzyme (ACE) activity and expression in numerous tissues, especially kidney, of non-obese diabetic mouse. Kidney, lung, pancreas, heart, liver and adrenal tissues from diabetic and control female NOD mice were homogenized for measurement of ACE activity, SDS-PAGE and Western blotting for ACE and ACE2, immunohistochemistry for ACE and angiotensins I, II and 1-7 and bradykinin quantification. ACE activity was higher in kidney, lung and adrenal tissue of diabetic mice compared with control mice. In pancreas, activity was decreased in the diabetic group. Western blotting analysis indicated that both groups presented ACE isoforms with molecular weights of 142 and 69 kDa and a decrease in ACE2 protein expression. Angiotensin concentrations were not altered within groups, although bradykinin levels were higher in diabetic mice. The immunohistochemical study in kidney showed an increase in tubular ACE expression. Our results show that the RAAS is affected by diabetes and the elevated ACE/ACE2 ratio may contribute to renal damage.

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Increased Aldosterone Levels in a Model of Type 2 Diabetes Mellitus

Cited by 30 publications

References 17 publications

Pharmacogenomic, Physiological, and Biochemical Investigations on Safety and Efficacy Biomarkers Associated with the Peroxisome Proliferator-Activated Receptor-γ Activator Rosiglitazone in Rodents: A Translational Medicine Investigation

Pharmacogenomic, Physiological, and Biochemical Investigations on Safety and Efficacy Biomarkers Associated with the Peroxisome Proliferator-Activated Receptor-γ Activator Rosiglitazone in Rodents: A Translational Medicine Investigation

Relationships Between Renin, Aldosterone, and 24-Hour Ambulatory Blood Pressure in Obese Adolescents

Renin-angiotensin system may trigger kidney damage in NOD mice

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