Angiotensin-(1–7) can interact with the rat proximal tubule AT4receptor system

This study was undertaken to identify the non-AT(1), non-AT(2) angiotensin receptor that mediates the ANG-(1-7) inhibitory action on rat proximal tubule transport processes. ANG-(1-7) inhibited nystatin-stimulated, ouabain-suppressible O(2) consumption (QO(2)) rates in freshly isolated rat proximal tubules (reflecting reduced basolateral Na(+)-K(+)-ATPase activity). Selective angiotensin-receptor subtype antagonists revealed that AT(1) and AT(4) receptors mediated the response of ANG-(1-7). Receptor autoradiography of the rat kidney demonstrated a high density of AT(1) and AT(4) receptors and no specific (125)I-ANG(1-7) binding sites. Competition assays in rat kidney sections indicated that ANG-(1-7) competed predominantly for the AT(1) receptor site, whereas its NH(2)-terminal-deleted metabolite, ANG-(3-7), competed primarily for the AT(4)-receptor site. Metabolism of (125)I-ANG-(1-7) in rat proximal tubules generated peptide fragments that included ANG-(3-7), with the pentapeptide producing a concentration-dependent inhibition of nystatin-stimulated proximal tubule QO(2) that was abolished by AT(4)-receptor blockade. These results suggest that the generation of ANG-(3-7) from the NH(2)-terminal metabolism of ANG-(1-7) caused the interaction of the parent peptide with the proximal tubule AT(4) receptor, which elicited a decrease in energy-dependent solute transport.