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P-590: Obesity regulates renal endothelin and endothelin ETA receptor expression in vivo. Differential effects of chronic ETA receptor blockade

Zhang, Jian ; d'Uscio, Livius V. ; Shaw, Sidney ; Münter, Klaus ; Klainguti, Michael ; Barton, Matthias

In: American Journal of Hypertension, 2001, vol. 14, no. S1, p. 227A-227A

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    Title
    • P-590: Obesity regulates renal endothelin and endothelin ETA receptor expression in vivo. Differential effects of chronic ETA receptor blockade
    Author
    • Zhang, Jian. Department of Medicine University Hospital Zurich, Zurich, Switzerland
    • d'Uscio, Livius V.. Department of Medicine University Hospital Zurich, Zurich, Switzerland
    • Shaw, Sidney. Department of Medicine University Hospital Zurich, Zurich, Switzerland
    • Münter, Klaus. Department of Medicine University Hospital Zurich, Zurich, Switzerland
    • Klainguti, Michael. Department of Medicine University Hospital Zurich, Zurich, Switzerland
    • Barton, Matthias. Department of Medicine University Hospital Zurich, Zurich, Switzerland
    Document Type
    • Postprint
    OAI-PMH Identifier
    • oai:doc.rero.ch:303326
    Summary
    ETA receptors have been implicated in obesity-associated hypertension (Hypertension 1999; 33: 1169). We characterized the renal endothelin system in diet-induced obesity and determined the effects of chronic treatment with the ETA antagonist darusentan. C57BL/6J mice were fed a standard diet (control) or a high-fat diet (Harlan TD88137) with or without darusentan (50 mg/kg/d, 30 wk). Total RNA was extracted from whole kidneys and mRNA expression of preproendothelin-1 (ppET-1), ETA receptors, and β-actin were determined by RT-PCR using mouse-specific primers. PCR-products were normalized vs. β-actin or 18S rRNA. Renal ET-1 protein was measured by RIA/HPLC. High fat diet increased body weight by 257% compared to 54% (control diet). Darusentan had no effect on body weight in obese mice (263%) and treatments had no effect on systolic blood pressure. Obesity was associated with upregulation of renal ETA receptors (144±5% vs 100±7%, p<0.05 vs. control) and to a lesser extent, preproendothelin-1 (113±5% vs.100±2%, p<0.05 vs. control). In obese mice chronic darusentan treatment in part prevented the ETA receptor upregulation (126% vs. 144±5%, p<0.05) but had no significant effect on ppET-1 mRNA expression (101±9 vs. 100±2%, n.s.). Renal ET-1 protein increased in obese animals (from 190±18 to 267±19 pg/g tissue, p<0.05 vs. control). This increase was not affected by concomitant darusentan treatment (n.s.). These data for the first time demonstrate that obesity in normotensive rats is associated with upregulation of renal ETA receptor expression suggesting that body weight per se affects ET receptor expression in the kidney. Our data further indicate that in this model ETA receptors control expression of the ETA receptor but not the ppET-1 gene, suggesting autocrine regulation in vivo. These mechanisms might contribute to the pathogenesis of obesity-associated diseases affecting the kidney and/or blood pressure