title: Conditional transgenic mice for studying the role of the glucocorticoid receptor in the renal collecting duct.
abstract: The mineralocorticoid receptor (MR) is a major regulator of renal sodium reabsorption and body fluid homeostasis. However, little is known about glucocorticoid receptor (GR)-dependent renal effects. Glucocorticoids may activate both receptors, so it is difficult to distinguish between MR- and GR-mediated effects in vivo. To overcome this complexity, we used a transgenic mouse model allowing conditional GR overexpression (doxycycline inducible TetON system, Hoxb7 promoter) in the renal collecting duct (CD) to identify GR-regulated genes involved in sodium transport in the CD. In microdissected cortical CD, induction of GR expression led (after 2 d of doxycycline) to increased alpha-epithelial sodium channel and glucocorticoid-induced leucine zipper and decreased abundance of with-no-lysine kinase 4 transcripts, without modification of Na,K-ATPase, serum- and glucocorticoid-kinase-1, or MR expression. No changes occurred in the upstream distal and connecting tubules [distal convoluted tubule (DCT), connecting tubule (CNT)]. Sodium excretion was unaltered, but the urinary aldosterone concentration was reduced, suggesting compensation of transitory extracellular volume expansion that subsequently disappeared. At steady state, i.e. after 15 d of doxycycline administration, transcript abundance remained altered in the CD, whereas mirror changes appeared in the DCT and CNT. Plasma aldosterone or glucocorticoids and blood pressure were all unaffected. These experiments show that: 1) GR, in addition to MR, controls epithelial sodium channel- and glucocorticoid-induced leucine zipper expression in vivo in the CD; 2) with-no-lysine kinase 4 is negatively controlled by GR; and 3) the DCT and CNT compensate for these alterations to maintain normal sodium reabsorption and blood pressure. These results suggest that enhanced GR expression may contribute to enhanced sodium retention in some pathological situations.
authors.affiliation: Institut Natíonal de la Santé et de la Recherche Medicalé Unité 772 College de France, 11 Place Marcelin Berthelot, 75005 Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Nguyen Dinh Cat
authors.forename: Antoine
authors.initials: A
authors.lastname: Ouvrard-Pascaud
authors.forename: François
authors.initials: F
authors.lastname: Tronche
authors.forename: Maud
authors.initials: M
authors.lastname: Clemessy
authors.forename: Daniel
authors.initials: D
authors.lastname: Gonzalez-Nunez
authors.forename: Nicolette
authors.initials: N
authors.lastname: Farman
authors.forename: Frederic
authors.initials: F
authors.lastname: Jaisser
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000235:genetics / Q000502:physiology; D004318:Doxycycline / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007685:Kidney Tubules, Collecting / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012084:Renin-Angiotensin System / Q000235:genetics; D012964:Sodium / Q000378:metabolism; D014162:Transfection; D019076:Transgenes / Q000187:drug effects; D014882:Water-Electrolyte Balance / Q000235:genetics
chemical_list: D011965:Receptors, Glucocorticoid; D012964:Sodium; D004318:Doxycycline