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A urine-concentrating defect in 11β-hydroxysteroid dehydrogenase type 2 null mice
Louise C Evans1, Dawn E Livingstone, Christopher J Kenyon
1BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, The Univ. of Edinburgh, 47, Little France Crescent, Edinburgh, UK EH16 4TJ.
American Journal of Physiology. Renal Physiology
|May 25, 2012
Summary
Mice lacking the HSD11B2 gene develop severe polyuria and polydipsia, leading to nephrogenic diabetes insipidus. This condition impairs the kidney's ability to concentrate urine, especially in older mice.
Area of Science:
- Endocrinology
- Nephrology
- Molecular Biology
Background:
- 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) protects mineralocorticoid receptors from glucocorticoids in aldosterone target tissues.
- Null mutations in HSD11B2 cause apparent mineralocorticoid excess, with hypertension linked to sodium retention and volume expansion.
- Previous studies suggested hypertension in Hsd11b2(-/-) mice reflects volume expansion, but impaired natriuresis indicated a potential urine concentrating defect.
Purpose of the Study:
- To investigate the urine concentrating defect in Hsd11b2(-/-) mice.
- To assess water turnover and the renal concentrating response to water deprivation in Hsd11b2(-/-) mice.
- To determine the underlying molecular mechanisms and age-related changes in renal water transport.
Main Methods:
- Assessment of water turnover and polyuria in Hsd11b2(-/-) mice and controls.
- Evaluation of the urine concentrating response to a 24-hour water deprivation challenge.
- Measurement of mRNA abundance for aquaporins (aqp2, aqp3, aqp4) and solute transporters (slc14a2, slc12a2).
- Administration of V2 receptor agonist desmopressin to assess response.
Main Results:
- Hsd11b2(-/-) mice exhibited a severe, progressive polyuric/polydipsic phenotype.
- Younger mice showed decreased aqp2 and aqp3 mRNA; older mice developed renal medulla atrophy and downregulation of multiple water transport genes.
- The concentrating response to water deprivation was impaired in older mice, and bumetanide's natriuretic effect was lost.
- Desmopressin failed to restore full urine concentrating capacity in older Hsd11b2(-/-) mice.
Conclusions:
- Hsd11b2(-/-) mice develop nephrogenic diabetes insipidus due to impaired renal water transport.
- Renal medullary atrophy in older mice is likely secondary to sustained polyuria.
- The study reveals a critical role for 11βHSD2 in maintaining renal water balance and preventing nephrogenic diabetes insipidus.
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