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Megalin binds and internalizes angiotensin-(1–7)

¹Tulane Hypertension and Renal Center of Excellence and Department of Physiology, Tulane University Health Sciences Center, ²Department of Medicine/Section of Nephrology, Tulane University Health Sciences Center, and Tulane Environmental Astrobiology Center, Center for Bioenvironmental Research, ³Department of Chemistry, Xavier University of Louisiana, and ⁴Veterans Affairs Medical Center, New Orleans, Louisiana

Submitted 19 April 2005 ; accepted in final form 14 December 2005

Megalin is a multiligand receptor heavily involved in protein endocytosis. We recently demonstrated that megalin binds and mediates internalization of ANG II. Although there is a strong structural resemblance between ANG II and ANG-(1–7), their physiological actions and their affinity for the angiotensin type 1 receptor (AT₁R) are dissimilar. Therefore, the hypothesis of the present work was to test whether megalin binds and internalizes ANG-(1–7). The uptake of ANG-(1–7) was determined by exposure of confluent monolayers of BN/MSV cells (a model representative of the yolk sac epithelium) to fluorescently labeled ANG-(1–7) (100 nM) and measurement of the amount of cell-associated fluorescence after 4 h by flow cytometry. Anti-megalin antisera and an AT₁R blocker (olmesartan) were used to interfere with uptake via megalin and the AT₁R, respectively. ANG-(1–7) uptake was prevented by anti-megalin antisera (63%) to a higher degree than olmesartan (13%) (P < 0.001). In analysis by flow cytometry of binding experiments performed in brush-border membrane vesicles isolated from kidneys of CD-1 mice, anti-megalin antisera interfered with ANG-(1–7) binding more strongly than olmesartan (P < 0.05 against positive control). Interactions of megalin with ANG-(1–7) at a molecular level were studied by surface plasmon resonance, demonstrating that ANG-(1–7) binds megalin dose and time dependently and with an affinity similar to ANG II. These results show that the scavenger receptor megalin binds and internalizes ANG-(1–7).

endocytosis; epithelial cells; angiotensin type 1 receptor; olmesartan

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