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.

Mineralocorticoid and Glucocorticoid Receptors Stimulate Epithelial Sodium Channel Activity in a Mouse Model of Cushing Syndrome

“…The channel can be activated by either receptors in a mouse cell line, 16 and there is evidence for functional crossover in MR knockout mice 39 and transgenic mice overexpressing GR in the collecting duct. 40 In contrast, however, ␣-ENaC expression was not stimulated by a GR-specific dosage of dexamethasone, 20 and collecting duct-specific deletion of MR prevents expression of ENaC. 41 In the present study, GR-dependent contraction of plasma volume predominated.…”

Sex-Specificity of Mineralocorticoid Target Gene Expression during Renal Development, and Long-Term Consequences

“…Thus, it is likely that a balance between activation of these two pathways could be established in the adult kidney, in a sex-specific manner. A previous study has readily demonstrated a differential activation of Sgk1 and Gilz between MRs and GRs in the kidney in a model of overexpression of renal GRs [48]. Moreover, there are reports indicating that GRs and ERs may also interact and modulate each other’s downstream signaling [49], and that sexually dimorphic actions of glucocorticoids exist [50] .…”

In vivo nuclear translocation of mineralocorticoid and glucocorticoid receptors in rat kidney: differential effect of corticosteroids along the distal tubule

“…Geering and coworkers (22) were the first to suggest that the occupancy of both receptors is necessary to achieve a full biological response. Although there is evidence for some functional compensation of the GR in MRϪ/Ϫ mice (48), both receptors appear to be important for the control of sodium transport in the ASDN, as indicated by recent findings in mouse models with targeted inactivation of the MR in the renal collecting system (46), overexpression of the GR in the collecting duct (42), or with pharmacological inhibition of either the MR or the GR in ACTH-induced Cushing's syndrome (2). Based on recent experiments in a mouse collecting duct cell line, Gaeggeler and coworkers (19) came up with the idea that the exclusive occupancy of MR provides a limited increase in sodium transport which is adequate for (circadian) maintenance requirements under low plasma aldosterone levels, while occupancy of both receptors would lead to the maximal response needed for maximum sodium retention under severe salt restriction and/or stress.…”