Megalin binds and internalizes angiotensin-(1-7)

Area of Science:

• Biochemistry
• Cell Biology
• Endocrinology

Background:

• Megalin is a crucial receptor for protein endocytosis.
• Previous research showed megalin internalizes angiotensin II (ANG II).
• Angiotensin-(1-7) (ANG-(1-7)) shares structural similarities with ANG II but has different physiological actions.

Purpose of the Study:

• To investigate whether megalin binds and internalizes ANG-(1-7).
• To compare the role of megalin versus the angiotensin type 1 receptor (AT(1)R) in ANG-(1-7) uptake.

Main Methods:

• Cellular uptake assays using fluorescently labeled ANG-(1-7) in BN/MSV cells.
• Flow cytometry analysis of ANG-(1-7) binding to kidney brush-border membrane vesicles.
• Surface plasmon resonance to study molecular interactions between megalin and ANG-(1-7).
• Inhibition studies using anti-megalin antisera and an AT(1)R blocker (olmesartan).

Main Results:

• Anti-megalin antisera significantly inhibited ANG-(1-7) uptake (63%) compared to olmesartan (13%).
• Megalin blockade more effectively reduced ANG-(1-7) binding to kidney brush-border membrane vesicles than AT(1)R blockade.
• Surface plasmon resonance confirmed dose- and time-dependent binding of ANG-(1-7) to megalin with affinity comparable to ANG II.

Conclusions:

• The scavenger receptor megalin actively binds and internalizes ANG-(1-7).
• Megalin plays a more significant role in ANG-(1-7) cellular uptake than the AT(1)R.
• These findings reveal a novel mechanism for ANG-(1-7) processing mediated by megalin.