NDT Advance Access originally published online on December 7, 2004
Nephrology Dialysis Transplantation 2005 20(2):312-318; doi:10.1093/ndt/gfh606
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Nephrol Dial Transplant Vol. 20 No. 2 © ERA–EDTA 2004; all rights reserved
Original Article
Influence of growth factors on the proliferation of vascular smooth muscle cells isolated from subtotally nephrectomized rats after endothelin or angiotensin II antagonism
1 Medical Clinic III, Department of Cardiology, Nephrology, Hypertension and Renal Failure, 2 Department of General Neurology, Hertie Institute for Clinical Brain Research and 3 Section of Radiobiology and Molecular Environmental Research, Department of Radiotherapy, Eberhard-Karls-University, D-72076 Tübingen, Germany
Correspondence and offprint requests to: Bernhard R. Brehm, MD, Hoppe-Seylerstr. 3, D-72076 Tübingen, Germany. Email: bernhard.brehm{at}onlinehome.de
Background. Cardiovascular disease is the most important cause of death in patients with end-stage renal disease. In uraemia, the renin–angiotensin–aldosterone and endothelin (ET) systems are activated. It is not known whether inhibition of these systems attenuates the proliferation of isolated smooth muscle cells of uraemic rats.
Methods. Subtotally nephrectomized (SNX) rats were treated with an ETA receptor antagonist, an ETAB receptor antagonist, the angiotensin type 1 (AT1) receptor antagonist losartan (all 10 mg/kg body weight/day) or the angiotensin-converting enzyme (ACE) inhibitor trandolapril (0.1 mg/kg body weight/day) or received no medication (SNX) for 12 weeks. Then, aortal smooth muscle cells (SMCs) were isolated and cultivated. After incubation of SMCs with different growth factors (5–7 days), proliferation was measured using a bromodeoxyuridine enzyme-linked immunosorbent assay (BrdU ELISA).
Results. Higher maximum levels of proliferation were found in SMCs from untreated SNX rats than in SMCs from control animals [platelet-derived growth factor-BB (PDGF-BB) 486.60±8.27 vs 346.74±4.60%, basic fibroblast growth factor (bFGF) 176.68±6.50 vs 123.71±1.49%, tumour necrosis factor-
(TNF-) 153.38±10.16 vs 122.27±1.41%]. Treatment with ET receptor antagonists or losartan attenuated growth factor-stimulated proliferation (PDGF-BB: ETA receptor antagonist, 135.71±1.08%; ETAB receptor antagonist, 122.72±0.58%; losartan: 103.69±1.83%, n = 8). SMCs from trandolapril-treated rats showed an increased response (PDGF-BB 663.48±7.00%, n = 8).
Conclusions. Treatment of SNX rats with ET receptor antagonists or losartan reduced growth factor-induced SMC proliferation in vitro. However, further investigations with uraemic patients have to clarify whether angiotensin or ET receptor antagonists inhibit the development of atherosclerosis.
Keywords: growth factors; proliferation; SMC; uraemia