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Effect of dopamine D3 receptor blockade on renal function and glomerular size in diabetic rats

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Abstract

Dopamine D2-like receptors, including D2, D3, and D4 receptors, are involved in the regulation of glomerular hyperfiltration due to diabetes mellitus. These hemodynamic alterations represent a risk factor for the later development of diabetic nephropathy. The aim of the present study was to determine whether the D3 receptor subtype modulates the diabetes-induced increase in glomerular filtration rate (GFR) in rats. Renal function was studied in Sprague–Dawley rats 14 days after induction of a moderate diabetes mellitus (DM) by streptozotocin and in non-diabetic controls (CON). Rats were orally treated either with the peripherally acting, selective dopamine D3 receptor antagonist BSF 135170 (BSF, 10 mg/kg per day for 2 weeks) or with vehicle (VHC). Perfusion-fixed kidneys were used for estimation of glomerular volume. In conscious rats, which were treated with BSF, the DM-induced increase in fluid intake, urinary output, and renal sodium excretion was significantly less pronounced than in the vehicle group (DM-VHC). In the clearance experiments, GFR in CON was about 0.84±0.04 ml/min per 100 g body weight. The DM-VHC group presented a significant glomerular hyperfiltration (1.09±0.04 ml/min per 100 g body weight). Treatment with BSF significantly lowered GFR towards levels of CON. The estimated glomerular volume was 0.73±0.03×106 μm3 in the CON-VHC group and 0.86±0.04×106 μm3 in the DM-VHC animals. Interestingly, treatment with BSF decreased the glomerular volume in both groups. Irrespective of BSF treatment, kidney wet weight related to body weight was about 36% higher in DM animals compared with CON animals. We conclude that dopamine D3 receptors represent a target for the modulation of diabetes-induced glomerular hyperfiltration. Therefore, the results encourage the testing of the possible beneficial effects of long-term D3 receptor blockade on the development of diabetic nephropathy.

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Acknowledgements

We thank Dr. R. Munschauer (ABBOTT GmbH&Co.KG, Ludwigshafen, Germany) and Dr. D. Starck (BASF AG, Ludwigshafen, Germany) for synthesizing BSF 135170 and Dr. A. Mack (Department of Anatomy, University of Tübingen, Germany) for helpful support in the morphological studies. Financial support for this study was provided by the BMBF (Grant No. 01EC9405), the IZKF Tübingen (Grant No. 01KS9602), and the Deutsche Forschungsgemeinschaft (DFG-Grant Mu 1297/1-2).

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Medicine, University of Tübingen, Wilhelmstrasse 56, 72074, Tübingen, Germany

    Gerd Luippold, Martina Beilharz & Bernd Mühlbauer

  2. Department of Pathology, Faculty of Medicine, University of Tübingen, 72074, Tübingen, Germany

    Manfred Wehrmann

  3. Neuroscience Discovery Research, ABBOTT GmbH&Co.KG, 67061, Ludwigshafen, Germany

    Liliane Unger & Gerhard Gross

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  1. Gerd Luippold
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  2. Martina Beilharz
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  4. Liliane Unger
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  6. Bernd Mühlbauer
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Correspondence to Gerd Luippold.

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Luippold, G., Beilharz, M., Wehrmann, M. et al. Effect of dopamine D3 receptor blockade on renal function and glomerular size in diabetic rats. Naunyn Schmied Arch Pharmacol 371, 420–427 (2005). https://doi.org/10.1007/s00210-005-1030-1

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  • DOI: https://doi.org/10.1007/s00210-005-1030-1

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