Proceedings of The Physiological Society
University of Manchester (2010) Proc Physiol Soc 19, PC219
Antioxidant Treatment Rescues Salt-Sensitive Hypertension and Impaired Natriuresis in 11??-HSD2 Heterozygote Mice
E. Craigie1,2, J. J. Mullins2, M. A. Bailey2
1. Department of Nephrology/Physiology, University College London, London, United Kingdom. 2. Molecular Physiology Group, University of Edinburgh, Edinburgh, United Kingdom.
11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) confers aldosterone specificity to the mineralocorticoid receptor by inactivating glucocorticoids. Mutations in HSD11B2 cause the hypertensive disorder of Apparent Mineralocorticoid Excess, and polymorphisms in the general population have been linked to salt-sensitive hypertension (SSH; 1). We have previously shown hsd11b2 heterozygote mice (hsd11b2+/-) have a SSH phenotype (2). There is strong evidence from published studies that SSH is linked to renal oxidative stress (OS) (3,4,5). We therefore assessed the impact of a high Na+ diet on a urinary marker of OS in hsd11b2+/- and control mice (hsd11b2+/+), and also the effects of antioxidant treatment on SSH. Urinary excretion of the OS marker 8-isoprostane (8-iso) was measured in male hsd11b2+/- and hsd11b2+/+ (both n=6). Mice were housed in metabolic cages and fed control diet (0.25% Na+) for 3 days of baseline measurements. Mice were then moved to a high Na+ diet (2.5%) and 8-iso excretion was measured over 3 weeks. In separate experiments, hsd11b2+/- and hsd11b2+/+ (both n=6) were housed in metabolic cages and fed control and high Na+ diet, as before. The antioxidant Tempol (2mmol/l) was administered in drinking water throughout. Daily Na+ excretion was measured for both Na+ diets, and at the end of the experiment mice were anaesthetised (Inactin, 100mg/kg IP) to measure arterial blood pressure (BP). Data are mean±SE; statistical comparisons were made using t-test or 2-way ANOVA. Urinary levels of 8-iso were similar between hsd11b2+/+ and hsd11b2+/- on a control diet (1807.2±440.2 vs 1901.2±367 pg/24h). High Na+ diet caused a significant increase in 8-iso levels for both groups on day 1 (7567.6±508.1 vs 7064.6±1231.1 pg/24h). During Tempol treatment daily urinary Na+ excretion was similar in both groups on a control diet. Na+ excretion increased rapidly on induction of the high Na+ diet; there was no difference between hsd11b2+/+ and hsd11b2+/- on day 1 (143.2±7.3 vs 146.5±10.2 µmol/24h/g). This contrasted to previous results without Tempol treatment where hsd11b2+/- displayed blunted natriuresis on a high Na+ diet on day 1 (2; 152.9±8.9 vs 106.2±11.9 µmol/24h/g). Tempol treatment resulted in similar BP between hsd11b2+/+ and hsd11b2+/- after 3 weeks on a high Na+ diet (88.2±2.3 vs 91.1±2.7mmHg) in contrast to previous studies with no treatment (2; 101.4±2.1 vs 87.5±1.54mmHg). In summary, a high Na+ diet increases urinary 8-iso excretion in hsd11b2+/+ and hsd11b2+/-. Administration of Tempol rescues the natriuresis and BP phenotypes of 11bhsd2+/- on a high Na+ diet. These results suggest that OS may be involved in the SSH phenotype of hsd11b2+/-, and that increased OS coupled with reduced 11β-HSD2 activity has negative effects for Na+ and BP homeostasis. This study has implications for treatment of SSH within the general population.
Where applicable, experiments conform with Society ethical requirements