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1 Tulane Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA, USA
2 Department of Chemistry, Xavier University of Louisiana, New Orleans, LA, USA
3 Department of Medicine/Section of Neprhology, Tulane University School of Medicine, New Orleans, LA, USA
4 Tulane Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA, USA; Department of Medicine/Section of Neprhology, Tulane University School of Medicine, New Orleans, LA, USA; Veterans Affairs Medical Center, New Orleans, LA, USA
* To whom correspondence should be addressed. E-mail: thammond{at}tulane.edu.
Megalin is an abundant membrane protein heavily involved in receptor-mediated endocytosis. The major functions of megalin in vivo remain incompletely defined as megalin typically faces specialized milieus such as glomerular filtrate, airways, epididymal fluid, thyroid colloid, and yolk sac fluid, which lack many of its known ligands. In the course of studies on Angiotensin II (Ang II) internalization we were surprised when only part of the uptake of labeled Ang II into immortalized yolk sac cells (BN-16 cells) was blocked by specific peptide inhibitors and direct competitors of the Angiotensin Type 1 Receptor (AT1R). This led us to test if megalin was a receptor for Ang II. Four lines of direct evidence demonstrate that megalin, and to a lesser extent its chaperone protein cubilin, are receptors for Ang II. First, in BN-16 cells anti-megalin and anti-cubilin antisera interfere with Ang II uptake. Second, also in BN-16 cells, pure Ang II competes for uptake of a known megalin ligand. Third, in proximal tubule cell brush border membrane vesicles extracted from mice, anti-megalin antisera interfere with Ang II binding. Fourth, purified megalin binds Ang II directly in surface plasmon resonance experiments. The finding that megalin is a receptor for Ang II suggests a major new function for the megalin pathway in vivo. These results also indicate that Ang II internalization in some tissues is megalin depedent and that megalin may play a role in regulating proximal tubule Ang II levels.
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