Jürgen Janke

Angiotensin Type 1 Receptor Blockers Induce Peroxisome Proliferator–Activated Receptor-γ Activity

Background—Angiotensin type 1 receptor (AT1R) blockers (ARB) have been shown to reduce the incidence of type 2 diabetes mellitus by an unknown molecular mechanism. The peroxisome proliferator–activated receptor-γ (PPARγ) is the central regulator of insulin and glucose metabolism improving insulin sensitivity. We investigated the regulation of PPARγ function by ARBs. Methods and Results—The ARBs irbesartan and telmisartan (10 μmol/L) potently enhanced PPARγ-dependent 3T3-L1 adipocyte differentiation associated with a significant increase in mRNA expression of the adipogenic marker gene adipose protein 2 (aP2), as measured by quantitative real-time polymerase chain reaction (irbesartan: 3.3±0.1-fold induction; telmisartan: 3.1±0.3-fold induction; both P <0.01). Telmisartan showed a more pronounced induction of aP2 expression in lower, pharmacologically relevant concentrations compared with the other ARBs. The ARB losartan enhanced aP2 expression only at high concentrations (losartan 100 μmol/L: 3.6±0.3-fold induction; P <0.01), whereas eprosartan up to 100 μmol/L had no significant effects. In transcription reporter assays, irbesartan and telmisartan (10 μmol/L) markedly induced transcriptional activity of PPARγ by 3.4±0.9-fold and 2.6±0.6-fold (P <0.05), respectively, compared with 5.2±1.1-fold stimulation by the PPARγ ligand pioglitazone (10 μmol/L). Irbesartan and telmisartan also induced PPARγ activity in an AT1R-deficient cell model (PC12W), demonstrating that these ARBs stimulate PPARγ activity independent of their AT1R blocking actions. Conclusions—The present study demonstrates that a specific subset of ARBs induces PPARγ activity, thereby promoting PPARγ-dependent differentiation in adipocytes. The activation of PPARγ demonstrates new pleiotropic actions of certain ARBs, providing a potential mechanism for their insulin-sensitizing/antidiabetic effects.

Angiotensin Blockade Prevents Type 2 Diabetes by Formation of Fat Cells

Obesity is the prime risk factor for the development of type 2 diabetes. Recent clinical trials have shown that blockade of the renin-angiotensin system, either by inhibiting the angiotensin-converting enzyme or blocking the angiotensin type 1 receptor, may substantially lower the risk for type 2 diabetes. The mechanism underlying this effect is unknown. Based on our recent observation that angiotensin II markedly inhibits adipogenic differentiation of human adipocytes via the angiotensin type I receptor and that expression of angiotensin II-forming enzymes in adipose tissue is inversely correlated with insulin sensitivity, we propose the hypothesis that blockade of the renin-angiotensin system prevents diabetes by promoting the recruitment and differentiation of adipocytes. Increased formation of adipocytes would counteract the ectopic deposition of lipids in other tissues (muscle, liver, pancreas), thereby improving insulin sensitivity and preventing the development of type 2 diabetes.

Dysregulation of the Circulating and Tissue-Based Renin-Angiotensin System in Preeclampsia

The renin–angiotensin system (RAS) participates in preeclampsia; however, the relative contributions from the circulating RAS and the tissue-based, uteroplacental RAS are unknown. We hypothesized that the tissue-based uteroplacental RAS is dysregulated in preeclampsia. We performed microarray and gene expression studies and confirmed the findings on the protein level by immunohistochemistry in ureteroplacental units from 10 preeclamptic women and 10 women with uneventful pregnancies. All of the women were delivered by cesarean section. We also analyzed plasma renin activity and circulating agonistic angiotensin II type 1 (AT1) receptor autoantibodies. In preeclampsia, we found that the angiotensin II AT1 receptor gene was 5-fold upregulated in decidua (maternal origin). We also found AT1 autoantibodies in preeclamptic women and in their offspring by neonatal cardiomyocyte bioassay compared with women with normal pregnancies and their infants (mother: 17.5±2.2 versus 0.05±0.4; fetus: 14.5±1.8 versus 0.5±0.5 &Dgr;bpm). Gene expressions for renin (35.0-fold), angiotensin-converting enzyme (2.9-fold), and angiotensinogen (8.9-fold) were higher in decidua than placenta (fetal origin) in both control and preeclamptic women, whereas the AT1 receptor was expressed 10-fold higher in placenta than in decidua in both groups. Our findings elucidate the ureteroplacental unit RAS in preeclamptic and normal pregnancies. We found that, in preeclampsia, the AT1 receptor expression is particularly high in decidua, combined with pregnancy-specific tissue RAS involving decidual angiotensin II production and AT1 autoantibodies. We also showed that AT1 autoantibodies cross the ureteroplacental barrier. These components could participate in the pathophysiology of preeclampsia.

Energy Metabolism in Human Renin-Gene Transgenic Rats Does Renin Contribute to Obesity?

Renin initiates angiotensin II formation and has no other known functions. We observed that transgenic rats (TGR) overexpressing the human renin gene (hREN) developed moderate obesity with increased body fat mass and glucose intolerance compared with nontransgenic Sprague-Dawley (SD) rats. The metabolic changes were not reversed by an angiotensin-converting enzyme inhibitor, a direct renin inhibitor, or by (pro)renin receptor blocker treatment. The obese phenotype in TGR(hREN) originated from higher food intake, which was partly compensated by increases in resting energy expenditure, total thermogenesis (postprandial and exercise activity), and lipid oxidation during the first 8 weeks of life. Once established, the difference in body weight between TGR(hREN) and SD rats remained constant over time. When restricted to the caloric intake of SD, TGR(hREN) developed an even lower body weight than nontransgenic controls. We did not observe significant changes in the cocaine and amphetamine-regulated transcript, pro-opiomelanocortin, both anorexigenic, or neuropeptide Y, orexigenic, mRNA levels in TGR(hREN) versus SD controls. However, the mRNA level of the agouti-related peptide, orexigenic, was significantly reduced in TGR(hREN) versus SD controls at the end of the study, which indicates a compensatory mechanism. We suggest that the human renin transgene initiates a process leading to increased and early appetite, obesity, and metabolic changes not related to angiotensin II. The mechanisms are independent of any currently known renin-related effects.

Influence of Salt Intake on Renin–Angiotensin and Natriuretic Peptide System Genes in Human Adipose Tissue

We tested the hypothesis that changes in sodium intake modulate adipose-tissue renin–angiotensin and natriuretic peptide system gene expression in humans. We studied 9 healthy young men in a metabolic ward at constant room temperature, humidity, and water, potassium, and calcium intake. Subjects were submitted to 4 different periods of sodium intake, and blood samples, microdialysis samples (interstitial fluid), and biopsies from subcutaneous abdominal adipose tissue were obtained at the end of the low-sodium period (0.7 mmol Na/kg per day) and at the end of the high-sodium period (7.7 mmol Na/kg per day). Urinary sodium excretion was 64±4 mmol per day with the low-sodium diet and 521±8 mmol per day with the high-sodium diet. Systemic and microdialysate sodium concentrations were similar with both interventions. With high-sodium intake, systemic renin activity and aldosterone levels were suppressed, angiotensin-converting enzyme activity did not change, and systemic levels of the atrial natriuretic peptide increased. High-sodium diet increased angiotensin-converting enzyme and atrial natriuretic peptide gene expression in adipose tissue. None of the other genes tested were influenced by changes in dietary sodium intake. Our findings suggest that the adipose-tissue renin–angiotensin system is not part of a feedback mechanism regulating sodium homeostasis and blood pressure. Systemic and adipose-tissue renin–angiotensin systems are regulated at least in part independently from each other. In contrast, systemic atrial natriuretic peptide and adipose-tissue atrial natriuretic peptide respond similarly to changes in sodium intake.

Influence of dietary fat ingestion on asymmetrical dimethylarginine in lean and obese human subjects

BACKGROUND AND AIMSnAsymmetrical dimethylarginine (ADMA) may contribute to hypertension and cardiovascular disease by decreasing NO formation. In diabetic patients, a high fat meal acutely increased plasma ADMA while impairing endothelial function. We hypothesized that chronic and acute increases in dietary fat intake augment ADMA also in lean and in obese subjects without diabetes.nnnMETHODS AND RESULTSnSeventeen lean and twelve obese volunteers were randomized to two weeks of isocaloric diets with approximately 20% or >40% calories from fat in a cross-over fashion. At the end of the high and low fat periods, volunteers received corresponding test meals. ADMA was measured by GC-MS/MS using a deuterated standard. Mean fasting plasma ADMA concentration was 0.52 (0.49-0.54; 95% CI) μmol/l in lean and 0.53 (0.50-0.55) μmol/l in obese subjects (pxa0=xa00.55). The two week high fat diet did not influence ADMA. Both test meals elicited a 6%increase in circulating ADMA in lean subjects. In obese subjects, plasma ADMA concentration did not change with the low fat meal, and decreased by approximately 4% with the high fat meal.nnnCONCLUSIONnOur findings challenge the idea that obesity and dietary fat intake have a major effect on plasma ADMA, at least in subjects without overt cardiovascular and metabolic disease. This finding is important with regard to dietary recommendations for weight loss. Overestimation of the influence of dietary fat intake and obesity on circulating ADMA in previous reports was most likely due to methodological issues concerning ADMA measurements.