Effect of dopamine D3 receptor blockade on renal function and glomerular size in diabetic rats.
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 x 10(6) microm3 in the CON-VHC group and 0.86+/-0.04 x 10(6) microm3 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.
Luippold
Gerd
G
Department of Pharmacology and Toxicology, Faculty of Medicine, University of Tübingen, Wilhelmstrasse 56, 72074 Tübingen, Germany, gerd.luippold@uni-tuebingen.de
Beilharz
Martina
M
Wehrmann
Manfred
M
Unger
Liliane
L
Gross
Gerhard
G
Mühlbauer
Bernd
B
D000818:Animals; D002417:Cattle; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004294:Domperidone / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology*; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D007677:Kidney Function Tests; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors*
D018492:Dopamine Antagonists; D050637:Receptors, Dopamine D3; D004294:Domperidone; D006220:Haloperidol