The effects of aldosterone are mediated via cytoplasmic mineralocorticoid receptors (MR) that control the transcriptional of genes such as that encoding the regulatory kinase SGK1 and, in aldosterone-stimulated cells, increased cellular SGK1 activity appears to stimulate Na+ retention via the epithelial Na+ channel (ENaC). Whilst SGK1 knock out mice do not normally display an overt phenotype, they cannot adequately increase renal Na+ retention when exposed to a low Na+ diet (1). Although, the MR can also be activated by glucocorticoid hormones in vitro (cortisol in humans, corticosterone in rodents), this does not occur in vivo since aldosterone-sensitive tissues express an enzyme, 11-βHSD2, that rapidly converts these hormones into inactive metabolites. 11-βHSD2 thus fulfils an important physiological role by effectively protecting the cells of the cortical collecting duct from circulating glucocorticoids. Very high levels of cortisol can, however, overwhelm this protective mechanism and, under such circumstances, glucocorticoids can evoke renal Na+ retention. This abnormal response is thought to underlie the fluid retention, oedema and hypertension seen in conditions, such as Cushing’s syndrome, that are characterised by glucocorticoid excess (2). The role of 11-βHSD2 has recently been clarified by studies of rats that have been genetically modified by the deletion of the gene encoding this enzyme (3). These animals express a complex phenotype that involves overt hypertension that is worsened by high Na+ intake and is associated with increased renal Na+ retention (3). Since abnormalities in SGK1 are known to disturb whole body Na+ balance, we have now explored the effects of 11-βHSD2 gene deletion upon renal SGK1 activity. Kidneys removed from 11-βHSD2 nul rats and wild type animals were therefore homogenised and extracted proteins subject to Western analysis / densitometry. Analysis of these proteins showed that the Thr346/356/366-phosphorylated from of the protein encoded by n-myc downstream regulated gene 1 (NDRG1) was ~2.5 fold more abundant in the tissue from 11-βHSD2 nul rats (Fig. 1). There was, however, there was no difference in the overall NDRG1 expression level (Fig 1) and analyses using an antibody against b-actin confirmed that equal amounts of protein had been loaded onto each gel (Fig 1). Deletion of the 11-βHSD2 thus causes increased phosphorylation of NDRG1-Thr346/356/366 and, since these residues are phosphorylated by SGK1 and not by other, closely related kinases (4), these data show that deletion of the 11-βHSD2 gene deletion is associated with an abnormally high level of renal SGK1 activity. Abnormal regulation of this kinase may therefore underlie the physiological abnormalities that have recently been documented in these animals (3).