The glucocorticoid receptor in the distal nephron is not necessary for the development or maintenance of dexamethasone-induced hypertension

Abstract

Glucocorticoids are used as a treatment for a variety of conditions and hypertension is a well-recognized side effect of their use. The mechanism of glucocorticoid-induced hypertension is incompletely understood and has traditionally been attributed to promiscuous activation of the mineralocorticoid receptor by cortisol. Multiple lines of evidence, however, point to the glucocorticoid receptor as an important mediator as well. We have developed a mouse model of glucocorticoid-induced hypertension, which is dependent on the glucocorticoid receptor. To determine the site(s) of glucocorticoid receptor action relevant to the development of hypertension, we studied glucocorticoid-induced hypertension in a mouse with a tissue-specific knockout of the glucocorticoid receptor in the distal nephron. Although knockout mice had similar body weight, nephron number and renal histology compared to littermate controls, their baseline blood pressure was mildly elevated. Nevertheless, distal nephron glucocorticoid receptor knockout mice and controls had a similar hypertensive response to dexamethasone. Urinary excretion of electrolytes, both before and after administration of glucocorticoid was also indistinguishable between the two groups. We conclude that the glucocorticoid receptor in the distal nephron is not necessary for the development or maintenance of dexamethasone-induced hypertension in our model.

Figure 1

Successful knockout of GR in the distal nephron. Kidney sections of Ksp Cre+ and Cre− GR^loxP/loxP control kidney were double stained with antibodies to aquaporin-2 and GR. The control kidney shows clear co-localization of GR in the distal nephron, while the KO mouse shows minimal co-localization in both low power and higher power images.

Figure 2

Sustained HTN in Ksp Cre + GR^loxP/loxP mice treated with DEX. Controls and Ksp Cre + GR^loxP/loxP mice (n=4/group) were treated with DEX 15 mg/L in the drinking water for 1 week and BP was monitored continuously by catheter. The 24 hour mean arterial pressure is presented. A. Baseline BP is elevated in Ksp Cre + GR^loxP/loxP mice compared to controls (p=0.032). B. There is no significant difference between the mean DEX-induced rise in BP in the 2 groups (p=0.54). *** p < 0.05.

Figure 3

Renal histology is similar in Ksp Cre + GR^loxP/loxP mice and controls. Shown are H & E stains of kidney cortex from male mice. A. Control 10x, B. Ksp Cre+ 10x, C. Control 40x, D. Ksp Cre+ 40x

Figure 4

No alteration in DEX-induced urinary electrolyte excretion in Ksp Cre + GR^loxP/loxP mice. Urine from male Ksp Cre + GR^loxP/loxP (n=6) and control (n=7) mice was collected prior to DEX and for the first 16 hours following DEX administration. *** p < 0.05