Renal functional effects of the highly selective AT(2)R agonist, β-Pro(7) Ang III, in normotensive rats

Recently, we designed a group of peptides by sequential substitution of the naturally occurring α-amino acid throughout the Ang III peptide sequence with the corresponding β-amino acid. β-Amino acid substitution at the proline residue of Ang III (β-Pro(7)-Ang III) resulted in a highly selective AT(2)R ligand, demonstrating remarkable selectivity for the AT(2)R in both binding and functional studies. To provide additional functional evidence for the suitability of β-Pro(7) Ang III as a novel AT(2)R agonist, we tested effects of acute systemic administration of β-Pro(7)-Ang III on renal hemodynamic and excretory function in anesthetized normotensive male and female rats. We also compared the natriuretic effects of acute intrarenal administration of native Ang III and β-Pro(7)-Ang III in the presence of systemic AT(1)R blockade in anesthetized female rats to allow for the differentiation of systemic versus direct intrarenal natriuretic actions of β-Pro(7)-Ang III. In both male and female rats, acute systemic administration of β-Pro(7)-Ang III elicited renal vasodilatation and natriuresis. Notably, greater renal vasodilatory effects were observed in female versus male rats at the highest dose of β-Pro(7)-Ang III administered. Moreover, intra-renal administration of β-Pro(7)-Ang III produced significant natriuretic effects in female rats and, like Ang III, evoked AT(2)R translocation to the apical plasma membrane in renal proximal tubular cells. Taken together, our findings support the use of β-Pro(7)-Ang III as a novel AT(2)R agonist and experimental tool for exploring AT(2)R function and its potential as a therapeutic target. Furthermore, our findings provide further evidence of a sex-specific influence of AT(2)R stimulation on renal function.