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Angiotensin II Receptor Subtypes AT1 and AT2 Are Down-Regulated by Angiotensin II through AT1 Receptor by Different Mechanisms¹

INSERM-INRA U-418, Hôpital Debrousse, Lyon, France

Address all correspondence and requests for reprints to: Dr. J. M. Saez, INSERM-INRA U-418, Hôpital Debrousse, 69322 Lyon Cedex 05, France.

The regulatory effects of angiotensin II (AngII) on its receptor subtypes, AT₁ and AT₂, were studied using cultured bovine adrenal cells (BAC), which express both receptor subtypes, and PC12W and R3T3 cells, which express only AT₂ receptors. In BAC, AngII caused a decrease in AT₁- and AT₂-binding sites and their corresponding messenger RNAs (mRNAs), but with different kinetics. AT₁-binding sites decreased by more than 50% within the first 3 h, whereas AT₁ mRNA started to decline after a lag period of 3 h. Both AT₂-binding sites and mRNA remained stable within the first 6 h of AngII treatment. Then, AT₂ mRNA decreased rapidly with an apparent half-life of 2–3 h, whereas AT₂-binding sites declined with an apparent half-life of about 16 h. Measurement of transcription rate and mRNA half-life by the [³H]uridine-thiouridine method revealed that AngII reduced by 90% the rate of AT₁ transcription, but had no effect on AT₁ mRNA half-life, whereas it slightly reduced AT₂ transcription, but markedly reduced AT₂ mRNA stability. All of the effects of AngII on both AT₁ and AT₂ receptors were blocked by losartan, indicating that they were mediated exclusively through the AT₁ receptor. In PC12W cells, AngII was unable to modify AT₂-binding sites or mRNA. Moreover, in BAC, [¹²⁵I]AngII was internalized through the AT₁ receptor, whereas occupancy of AT₂ receptors in either BAC or PC12W did not produce internalization of the hormone. These results indicate that AngII, through the AT₁ receptor, down-regulates both AT₁ and AT₂, but by different mechanisms; AT1 receptor is regulated through internalization-degradation of the occupied receptor and inhibition of transcription, whereas AT2 receptor is regulated mainly by decreasing the stability of its mRNA. Moreover, the phorbol ester phorbol 12-myristate 13-acetate mimicked most of the effects of AngII in BAC and decreased both AT₂-binding sites and mRNA on PC12W cells, indicating that the hormonal regulation of both AT₁ and AT₂ receptors is mediated through protein kinase C activation.

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