Metabolism alters the selectivity of angiotensin-(1-7) receptor ligands for angiotensin receptors

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38 Scopus citations

Abstract

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 languageEnglish (US)
Pages (from-to)1377-1386
Number of pages10
JournalJournal of the American Society of Nephrology
Volume11
Issue number8
StatePublished - Aug 1 2000
Externally publishedYes

ASJC Scopus subject areas

  • Nephrology

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