Regulation of Angiotensin II Receptor Subtypes by Dexamethasone in Rat Mesangial Cells

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Abstract
Abstract The objective of this study was to examine the role of dexamethasone on the expression of angiotensin II (Ang II) receptors in cultured rat mesangial cells. Dexamethasone caused concentration- and time-dependent decreases in 125 I–[Sar 1 ,Ala 8 ]Ang II binding that were prevented by glucocorticoid receptor inhibition with mifepristone. A lag time of 24 hours and a dexamethasone concentration of at least 10 nmol/L were necessary for this effect to occur. Dexamethasone-induced reduction of 125 I–[Sar 1 ,Ala 8 ]Ang II binding resulted from decreased Ang II type 1 (AT 1 ) receptor density. No change in the apparent dissociation constant was observed. Dexamethasone also markedly inhibited Ang II–dependent inositol phosphate accumulation. Both reverse transcription–polymerase chain reaction and Northern blot analysis using specific short probes from the 3′ noncoding region of the cDNA demonstrated the presence of AT 1A and AT 1B receptor mRNAs in rat mesangial cells, with a slight predominance of AT 1B . Therefore, we studied the effect of dexamethasone on the expression of these two subtypes in rat mesangial cells. Dexamethasone produced a time-dependent decrease of AT 1B receptor mRNA that was apparent after 6 hours of incubation, whereas AT 1A receptor mRNA did not change. Mifepristone also suppressed the dexamethasone-induced decrease in AT 1B receptor mRNA. In conclusion, glucocorticoids diminish Ang II receptor density at the mesangial cell surface through a mechanism that implies successive interaction with the glucocorticoid receptor and specific reduction in AT 1B receptor mRNA expression. This differential regulation of both AT 1 receptor subtypes might allow glucocorticoids to exert adjusted effects in their various target tissues.

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