Effects of chronic SDMA infusion on glomerular filtration rate, blood pressure, myocardial function and renal histology in C57BL6/J mice

Abstract

Symmetrical dimethylarginine (SDMA), the structural isomer of the nitric oxide synthase inhibitor asymmetrical dimethylarginine, has long been regarded as an inert substance. Recent epidemiological and preclinical data suggest that it might be involved in the pathophysiology of renal and cardiovascular diseases. Therefore, we aimed to investigate the effect of chronic SDMA infusion on renal and cardiac function in mice. Eight-week-old male C57Bl/6 mice received vehicle-controlled infusion of SDMA (250 µmol/kg/days) for 28 days using osmotic minipumps (n = 24/group). The following parameters were monitored: glomerular filtration rate (GFR; fluoresceinyl thiocarbamoyl-inulin excretion kinetic), cardiac function (echocardiography) and blood pressure (tail cuff). Blood samples for SDMA determination were obtained at baseline, 2 and 4 weeks. Mice were euthanized at 4 weeks to obtain tissue for renal histology. Chronic SDMA infusion led to a significant increase of SDMA levels from 0.26 ± 0.10 to 3.49 ± 1.66 µmol/L (P < 0.001) at 4 weeks. Despite this SDMA increase, the GFR did not change (1224 ± 351 versus 1017 ± 345 mL/min/g body weight, n.s.) at 4 weeks, when compared with baseline. We did not find any histological changes, particularly no effect on fibrosis or endothelias nitric oxide synthase expression. There was neither an effect of SDMA on systolic blood pressure (106 ± 12 versus 111 ± 18 mmHg, n.s.) nor on ejection fraction (54.2 ± 1.7 versus 58.4 ± 1.9%, n.s.). Based on our experiments, it seems unlikely that chronically elevated SDMA alone has an effect on renal and cardiac function in otherwise healthy mice. Future studies have to clarify the potential pathophysiological role of SDMA in cardiovascular disease.