Renal functional effects of the highly selective AT2R agonist, β-Pro7 Ang III, in normotensive rats

Abstract

Recently, we designed peptides by sequential substitution of naturally occurring a-amino acid throughout the Ang III peptide sequence with the corresponding b-amino acid. b-amino acid substitution at the proline residue of Ang III (b-Pro⁷-Ang III) resulted in a highly selective AT₂R ligand, demonstrating remarkable selectivity for the AT₂R in both binding and functional studies. To provide additional functional evidence for the suitability of β-Pro⁷ Ang III as a novel AT₂R agonist, we tested the effects of acute systemic administration of β-Pro⁷-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-Pro⁷-Ang III in the presence of systemic AT₁R blockade in anesthetized female rats to allow for the differentiation of systemic versus direct intrarenal natriuretic actions of β-Pro⁷-Ang III. In both male and female rats, acute systemic administration of b-Pro⁷-Ang III elicited renal vasodilatation and natriuresis. Notably, greater renal vasodilatory effects were observed in female versus male rats at the highest dose of b-Pro⁷-Ang III administered. Moreover, intra-renal administration of b-Pro⁷-Ang III produced significant natriuretic effects in female rats and, like Ang III, evoked AT₂R translocation to the apical plasma membrane in renal proximal tubular cells. Taken together, our findings support the use of β-Pro⁷-Ang III as a novel AT₂R agonist and experimental tool for exploring AT₂R function and its potential as a therapeutic target. Furthermore, our findings provide further evidence of a sex-specific influence of AT₂R stimulation on renal function.