The present study examined whether metabolism of the putative angiotensin-(1-7) receptor agonist and antagonist [angiotensin-(1-7) and D- alanine7 angiotensin-(1-7), respectively] altered their ability to interact with angiotensin AT1, AT2, and AT4 receptor subtypes. Both angiotensin-(1- 7) and D-alanine7 angiotensin-(1-7) competed with low affinity for 125I- sarcosine1, isoleucine8 angiotensin II binding to AT1 and AT2 receptors in rat liver and adrenal medulla membranes, respectively, and competed with low affinity for 125I-angiotensin IV binding to AT4 receptors in bovine kidney epithelial cell membranes. In vitro renal metabolism of the angiotensin-(1-7) receptor ligands (incubating peptides with rat cortical tissue homogenates) had minimal influence on low-affinity binding to AT1 and AT1 receptors, yet caused a significant and dramatic shift toward high- affinity binding for AT4 receptors. Low-affinity angiotensin II binding to the AT4 receptor was also shifted toward high-affinity binding following renal metabolism of the peptide. Conversely, angiotensins with high affinity for the AT4 receptor (e.g., angiotensin IV) were shifted toward low-affinity binding states following peptide metabolism. Incubation of 125I- angiotensin-(1-7) with rat cortical tissue generated the high-affinity AT4 receptor ligand 125I-angiotensin-(3-7), whereas the renal metabolism of 125I-angiotensin II generated both 125I-angiotensin-(3-7) and 125I- angiotensin IV. These results reveal that renal metabolism of angiotensin-(1- 7) receptor ligands and angiotensin II yields products that have high affinity for the AT4 receptor and could potentially contribute to the biologic actions of the parent peptide in the kidney.
|Original language||English (US)|
|Number of pages||10|
|Journal||Journal of the American Society of Nephrology|
|State||Published - Aug 1 2000|
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