Glomerular effects of angiotensin II: a reappraisal based on studies with non-peptide receptor antagonists

Abstract

Aim: To examine the glomerular effects of angiotensin II (Ang II).

Method: A survey of recent studies that have provided relevant information.

Results: Glomeruli and mesangial cells of murine and human origin have receptors for Ang II (AT receptors) that are linked to phospholipase C. The dissociation constant (Kd) for these receptors is in the nanomolar range, and they are denser in freshly isolated glomeruli than in cultured mesangial cells. Pharmacological studies with the AT1 receptor, using losartan and its metabolite E3174, and with the AT2 receptor using PD 123177 and CGP 42112A, have shown that glomerular receptors for Ang II belong to the AT1 type. Furthermore, all the functional effects of Ang II in glomeruli and mesangial cells, including a rise in intracellular calcium, the stimulation of prostaglandin and protein synthesis, and glomerular vasoreactivity, are mediated by the AT1 receptor. [3H]-losartan binds specifically to mesangial cells but with different parameters from those observed for [125I]-Ang II. Losartan and E 3174 behave as non-competitive antagonists. Losartan exhibits some intrinsic effects but only at high concentrations not likely to be reached in vivo at normal doses. AT1 receptors in glomeruli are downregulated by plasma concentrations of Ang II and losartan.

Conclusions: These results demonstrate that the cellular mode of action of Ang II in glomeruli is mediated by the AT1 receptor type.