Impairment of Sodium Balance in Mice Deficient in Renal Principal Cell Mineralocorticoid Receptor
- 1 June 2007
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of the American Society of Nephrology
- Vol. 18 (6), 1679-1687
- https://doi.org/10.1681/asn.2006090975
Abstract
Germline inactivation of the mineralocorticoid receptor (MR) gene in mice results in postnatal lethality as a result of massive loss of sodium and water. The knockout mice show impaired epithelial sodium channel (ENaC) activity in kidney and colon. For determination of the role of renal MR in aldosterone-driven ENaC-mediated sodium reabsorption, mice with principal cell MR deficiency were generated using the Cre-loxP system. For driving Cre recombinase expression in principal cells, the regulatory elements of the mouse aquaporin 2 (AQP2) gene were used. Mutant mice (MRAQP2Cre) were obtained by crossing AQP2Cre mice with mice that carried a conditional MR allele. Under standard diet, MRAQP2Cre mice develop normally and exhibit unaltered renal sodium excretion but show strongly elevated aldosterone levels. Increased renal sodium and water excretion, resulting in continuous loss of body weight, occur under low-sodium diet. Immunofluorescence revealed that the loss of MR and apical ENaC staining is restricted to principal cells of the collecting duct (CD) and late connecting tubule (CNT) and that MR is crucial for ENaC trafficking to the apical membrane. These results demonstrate that inactivation of MR in CD and late CNT can be compensated under standard diet but no longer when sodium supply is limited. Because the mutant mice show preserved renal ENaC activity, this study provides evidence that the late distal convoluted tubule and early CNT can compensate to a large extent deficient ENaC-mediated sodium reabsorption in late CNT and CD.Keywords
This publication has 31 references indexed in Scilit:
- Lessons from Mouse Mutants of Epithelial Sodium Channel and Its Regulatory ProteinsJournal of the American Society of Nephrology, 2005
- Collecting duct-specific knockout of endothelin-1 alters vasopressin regulation of urine osmolalityAmerican Journal of Physiology-Renal Physiology, 2005
- Altered Renal Distal Tubule Structure and Renal Na+ and Ca2+ Handling in a Mouse Model for Gitelman’s SyndromeJournal of the American Society of Nephrology, 2004
- Na channels in the rat connecting tubuleAmerican Journal of Physiology-Renal Physiology, 2004
- Functional expression of a pseudohypoaldosteronism type I mutated epithelial Na+ channel lacking the pore-forming region of its α subunitJCI Insight, 1999
- Inducible site-specific recombination in the brainJournal of Molecular Biology, 1999
- Prostaglandins in macula densa functionKidney International, 1998
- Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1Nature Genetics, 1996
- Cell-specific expression of epithelial sodium channel alpha, beta, and gamma subunits in aldosterone-responsive epithelia from the rat: localization by in situ hybridization and immunocytochemistry.The Journal of cell biology, 1994
- Pharmacological and functional characterization of human mineralocorticoid and glucocorticoid receptor ligandsEuropean Journal of Pharmacology: Molecular Pharmacology, 1993