Proceedings of The Physiological Society

University of Manchester (2010) Proc Physiol Soc 19, PC248

Poster Communications

Progression of medullary atrophy and a urine concentrating defect in 11??-Hydroxysteroid Dehydrogenase Type 2 Knockout mice

L. C. Evans1, J. J. Mullins1, C. J. Kenyon1, M. A. Bailey1

1. Centre for Cardiovascular Science, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom.

Cortisol inactivation is catalysed by 11β-Hydroxysteroid Dehydrogenase Type 2 (11βHSD2). In aldosterone target tissues co-expression of 11βHSD2 and mineralocorticoid receptors (MR) protects the receptor from activation by glucocorticoids. In the syndrome of Apparent Mineralocorticoid Excess, mutations in HSD11B2 cause hypertension which is thought to be driven by volume expansion secondary to Na+ retention[1]. 11βHSD2-/- mice are hypertensive but paradoxically volume contracted[2]. The uncoupling of Na+ and water reabsorption suggests a urine concentrating defect in the mice. >180d 11βHSD2-/- mice are indeed polyuric and polydipsic[3]. The temporal relationship between altered water homeostasis and renal structure is unclear, and was therefore assessed in the present study. Male 11βHSD2-/- mice and C57/Bl6 controls aged <100d and >180d (n=6-7 per group) were individually housed in metabolic cages and water turnover measured over 4 consecutive days. Mice were culled by decapitation and kidneys and trunk blood collected. Kidneys were formalin fixed; gross histological damage was scored in a blinded fashion on a scale of 0-3, 3 representing severe atrophy. Renal sections were H+E stained for detailed evaluation (10 images per mouse). Plasma AVP was measured by radioimmunoassay. Data are presented as median±range or mean±S.E.M and statistical analysis performed using unpaired t-test, 1way ANOVA and Bonferroni post test as appropriate. 11βHSD2-/- mice aged <100d had structurally normal kidneys under both gross and fine histological evaluation. However, 4 of 7 null mice had significant polyuria (5.0±0.1 vs 1.3±.02ml/24h P<0.0001) and polydipsia (8.4±0.2 vs 4.0±0.01ml/24hr P<0.0001) relative to age matched controls. Circulating AVP levels were significantly higher in 11βHSD2-/- mice (45.1±5.1 vs 18.6±1.8pg/ml P=0.0031). In the >180d age group, increased water turnover was evident in all of the 11βHSD2-/- mice. Polyuria (12.3±0.1 vs 2.3±0.1ml/24hr P<0.0001) and polydipsia (15.8±0.1 vs 5.1±0.2ml/24hr P<0.0001) were more severe than in younger mice. Histologically, medullary atrophy was evident in all of the kidneys (score=3±1) and at the fine level there was evidence of tubular dilation. Control kidneys were normal at both gross (score=1±1) and fine levels. In conclusion, 11βHSD2-/- mice display a derangement in water homeostasis. Initially augmented water turnover, observed in the majority of <100d 11βHSD2-/-, occurred in the absence of renal injury. More severe polyuria was associated with medullary atrophy in older mice. The augmented AVP levels in 11βHSD2-/- mice suggest a renal component to the polyuria. Although we cannot define the cause of the medullary atrophy at this point, we postulate that it may reflect renal hypoxia, possibly due to peritubular capillary compression by the dilated tubules observed in the older mice[4].

Where applicable, experiments conform with Society ethical requirements