These actions exerted by cortisol are mediated by two brain corticosteroid receptor types: the high affinity mineralocorticoid (MR) and the low affinity glucocorticoid receptor (GR). Dexamethasone is a potent GR agonist with affinity to MR. Administration of dexamethasone in the evening results in a significant suppression of the morning cortisol awakening response (CAR).

Here we tested the involvement of MR variants in this effect of dexamethasone LY2090314 molecular weight in 218 young healthy subjects (125 females, all using oral contraceptives). For this purpose we determined two single nucleotide polymorphisms (SNPs) in the MR gene, the previously

described MRI180V (rs5522) and the MR-2G/C (rs2070951), which both affect in vitro the transactivational capacity of VE-821 purchase the MR in response to either cortisol or dexamethasone.

Administration of a low dose dexamethasone (0.25 mg) at 2300 h resulted in a significant suppression of the cortisol awakening response (CAR). Both SNPs modulated the suppression of the CAR after dexamethasone significantly and in a sex specific manner. Suppression of the CAR was highest in the female MR-2G/C GG subjects while in mate GG subjects the dexamethasone suppression of the CAR was attenuated compared to the MR-2G/C GC and CC groups. For the MRI180V, mate AA subjects showed after dexamethasone a higher CAR than AG subjects while this effect was not observed in females. The SNPs had no significant influence

on the CAR without prior dexamethasone treatment.

The association of the CAR with functional MR gene variants only in dexamethasone treated subjects suggests the involvement of MR in dexamethasone induced suppression of morning cortisol. (c) 2009 Elsevier Ltd. All rights reserved.”
“Inflammatory responses in the kidney lead to tubulointerstitial fibrosis, a common feature of chronic kidney diseases. Here we examined the role of prostaglandin E-2 (PGE(2)) in the development of tubulointerstitial fibrosis. In the kidneys of wild-type mice, unilateral ureteral

obstruction leads to progressive tubulointerstitial fibrosis with macrophage infiltration and myofibroblast Momelotinib chemical structure proliferation. This was accompanied by an upregulation of COX-2 and PGE(2) receptor subtype EP4 mRNAs. In the kidneys of EP4 gene knockout mice, however, obstruction-induced histological alterations were significantly augmented. In contrast, an EP4-specific agonist significantly attenuated these alterations in the kidneys of wild-type mice. The mRNAs for macrophage chemokines and profibrotic growth factors were upregulated in the kidneys of wild-type mice after ureteral obstruction. This was significantly augmented in the kidneys of EP4-knockout mice and suppressed by the EP4 agonist but only in the kidneys of wild-type mice. Notably, COX-2 and MCP-1 proteins, as well as EP4 mRNA, were localized in renal tubular epithelial cells after ureteral obstruction.