Impairment of sodium balance in mice deficient in renal principal cell mineralocorticoid receptor.
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 (MR(AQP2Cre)) were obtained by crossing AQP2Cre mice with mice that carried a conditional MR allele. Under standard diet, MR(AQP2Cre) 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.
Ronzaud
Caroline
C
Division of Molecular Biology of the Cell I (A020), German Cancer Research Center, Im Neuenheimer Feld 581, 69120 Heidelberg, Germany.
Loffing
Johannes
J
Bleich
Markus
M
Gretz
Norbert
N
Gröne
Hermann-Josef
HJ
Schütz
Günther
G
Berger
Stefan
S
D000450:Aldosterone / Q000097:blood; D000821:Animal Feed; D000818:Animals; D051399:Aquaporin 2 / Q000235:genetics; D003106:Colon / Q000378:metabolism; D004039:Diet, Sodium-Restricted; D004326:Drinking / Q000502:physiology; D053503:Epithelial Sodium Channels / Q000378:metabolism; D005260:Female; D019426:Integrases / Q000235:genetics; D007685:Kidney Tubules, Collecting / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018161:Receptors, Mineralocorticoid / Q000235:genetics* / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*; D014882:Water-Electrolyte Balance / Q000502:physiology
C496024:Aqp2 protein, mouse; D051399:Aquaporin 2; D053503:Epithelial Sodium Channels; D018161:Receptors, Mineralocorticoid; D000450:Aldosterone; D012964:Sodium; C045073:Cre recombinase; D019426:Integrases