Key result
Exposure to angiotensin II, losartan, or EXP-3174 differentially regulated AT1 receptor binding sites, with downregulation associated with increased relative internalization rather than mRNA changes.
Angiotensin II and losartan binding sites exhibit different regulatory mechanisms in response to ANG II, losartan, and its metabolite EXP-3174, with downregulation of AT1 receptors associated with increased internalization rather than changes in mRNA expression.
Animal data on AT1 internalization do not guide therapy; leaves open human translational relevance.
The aim of the present report was to examine the effect of several agents on angiotensin II (ANG II) and losartan receptors using 125I-[Sar1,Ala8]ANG II and [3H]losartan as radiolabeled ligand, respectively. ANG II receptors were downregulated in glomeruli from rats infused with ANG II during 3 wk or rats receiving losartan orally during 1 wk. The number of sites (Bmax) was reduced, but the dissociation constant (Kd) value was unchanged. Losartan receptors were downregulated in glomeruli from rats receiving losartan, but remained unchanged in glomeruli from rats infused with ANG II. Since in vivo administration of losartan results in increase of plasma ANG II and formation of metabolites, in vitro studies using human mesangial cells were performed to better analyze the present findings. Treatment of mesangial cells during 4 days by ANG II, losartan, or its metabolite, EXP-3174, also produced downregulation of 125I-[Sar1,Ala8]ANG II binding sites with a decreased Bmax and unchanged Kd value. Only treatment of mesangial cells by ANG II or EXP-3174 produced downregulation of [3H]losartan binding sites. In contrast, exposure of these cells to losartan resulted in upregulation of [3H]losartan binding sites. Under all conditions, only Bmax was modified. Whereas internalization of [3H]losartan in mesangial cells was negligible under all experimental conditions, there was an increase of the percentage of internalized 125I-[Sar1,Ala8]ANG II after exposure of the cells to ANG II or AT1 antagonists. No change was observed in mesangial cell AT1 receptor mRNA levels. This study demonstrates that 1) AT1 mRNA is expressed in human mesangial cells; 2) the characteristics of 125I-[Sar1,Ala8]ANG II and [3H]losartan binding sites in rat glomeruli and human mesangial cells are different, with Kd and Bmax values greater in both preparations when [3H]losartan was utilized; 3) both types of binding sites obey different regulations, and the effects of losartan in vivo are due in part to the associated increase in plasma ANG II levels and the transformation of the drug into its metabolite, EXP-3174; 4) downregulation of AT1 receptors does not depend on changes in mRNA expression but is associated with increased relative internalization.
No takes yet. Share an insight, caveat, or question.
Chansel et al. (1994) studied this question. Angiotensin II, losartan, or EXP-3174 was evaluated on Regulation of angiotensin II and losartan binding sites (Bmax and Kd). Exposure to angiotensin II, losartan, or EXP-3174 differentially regulated AT1 receptor binding sites, with downregulation associated with increased relative internalization rather than mRNA changes.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: