Abstract
11β-Hydroxysteroid dehydrogenases (11beta-HSD) modulate mineralocorticoid receptor transactivation by glucocorticoids and regulate access to the glucocorticoid receptor. The isozyme 11beta-HSD2 is selectively expressed in mineralocorticoid target tissues and its activity is reduced in various disease states with abnormal sodium retention and hypertension, including the apparent mineralocorticoid excess. As 50% of patients with essential hypertension are insulin resistant and hyperinsulinemic, we hypothesized that insulin downregulates the 11beta-HSD2 activity. In the present study we show that insulin reduced the 11beta-HSD2 activity in cancer colon cell lines (HCT116, SW620 and HT-29) at the transcriptional level, in a time and dose dependent manner. The downregulation was reversible and required new protein synthesis. Pathway analysis using mRNA profiling revealed that insulin treatment modified the expression of the transcription factor family C/EBPs (CCAAT/enhancer-binding proteins) but also of glycolysis related enzymes. Western blot and real time PCR confirmed an upregulation of C/EBP beta isoforms (LAP and LIP) with a more pronounced increase in the inhibitory isoform LIP. EMSA and reporter gene assays demonstrated the role of C/EBP beta isoforms in HSD11B2 gene expression regulation. In addition, secretion of lactate, a byproduct of glycolysis, was shown to mediate insulin-dependent HSD11B2 downregulation. In summary, we demonstrate that insulin downregulates HSD11B2 through increased LIP expression and augmented lactate secretion. Such mechanisms are of interest and potential significance for sodium reabsorption in the colon.
Highlights
The mineralocorticoid receptor (MR) is essential for renal sodium handling in epithelial tissues such as colon and kidney and for blood pressure control in humans
At a concentration of 1027 M, insulin decreased the CCAAT/enhancer binding proteins (C/EBPs) alpha mRNA by 51% (p,0.01), whereas C/EBP delta mRNA expression was unchanged. These results show that insulindependent reduction of HSD11B2 mRNA, correlates with the expression pattern of 2 out of 3 investigated members of the C/ EBP family of transcription factors in HT-29 cells
Insulin-dependent regulation of HSD11B2 The present investigation revealed in three different human cell lines, that insulin reduces the activity of 11beta-HSD2
Summary
The mineralocorticoid receptor (MR) is essential for renal sodium handling in epithelial tissues such as colon and kidney and for blood pressure control in humans. The mechanism allowing aldosterone to be the preferred ligand for the MR in vivo, despite the higher concentrations of cortisol is an enzyme which inactivates cortisol, in MR expressing cells [2]. This enzyme, 11bhydroxysteroid dehydrogenase type 2 (11beta-HSD2) is encoded by the HSD11B2 gene and converts biologically active cortisol into cortisone, a steroid with negligible affinity and activation potential for the MR [3]. A reduced activity of 11betaHSD2 causes cortisol-mediated MR activation, leading to renal sodium retention, suppression of renin and a salt-sensitive increase in blood pressure [4,5]
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