Potassium Negatively Regulates Angiotensin II Type 1 Receptor Expression in Human Adrenocortical H295R Cells

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Abstract
Abstract We have previously shown that the human adrenocortical H295R cell line expresses the type 1 angiotensin II receptor (AT 1 -R) and that expression of this receptor is downregulated at the level of mRNA by forskolin or dibutyryl-cAMP as well as by angiotensin II (Ang II). In this study we examine the effects of K + on both AT 1 -R mRNA and receptors, as monitored through 125 I–Ang II binding in the presence of PD 123319. After treatment with a maximal stimulatory steroidogenic dose of K + (14 mmol/L), H295R cells showed an increase in cytosolic free Ca 2+ from 113 to 212 nmol/L. Unlike the effects of Ang II, this increase could be abolished by pretreatment with the Ca 2+ channel antagonist nifedipine (1 μmol/L). AT 1 -R mRNA levels also fell in response to elevated extracellular K + in a dose-dependent ( K d , 9 mmol/L; maximal fall in message at 12 mmol/L) and time-dependent (maximum 50% at 12 hours) manner. The change in AT 1 -R mRNA level was less rapid than that in response to activation of phosphoinositidase C by Ang II or adenylyl cyclase by forskolin or by dibutyryl-cAMP. Unlike the action of Ang II but similar to the action of forskolin or dibutyryl-cAMP, the action of K + was sustained. Changes in mRNA level in response to treatment with K + , Ang II, or dibutyryl-cAMP were also paralleled by changes in 125 I–Ang II binding in each case. The mechanism of action of K + on AT 1 -R mRNA also appears to be mediated through the opening of voltage-sensitive channels on the plasma membrane because the drop in AT 1 -R mRNA was similarly abolished by the Ca 2+ channel blocker nifedipine. In conclusion, our findings show that AT 1 -R mRNA levels can be controlled through a Ca 2+ -dependent signaling pathway, as well as through phosphoinositidase C or adenylyl cyclase signaling pathways, and that these changes in mRNA level underlie a corresponding change in receptor protein at the cell surface.