Angiotensin‐converting enzyme 2 enhances megalin‐mediated albumin endocytosis in proximal tubule cells by restraining Angiotensin II/AT1R

Proximal tubule epithelial cell (PTEC) albumin transport efficiently prevents albuminuria under physiological conditions. This process occurs through a receptor-mediated endocytosis, being megalin, cubilin and amnionless the receptor complex involved. Evidence suggests that renin-angiotensin system (RAS) components regulate albumin transport in proximal tubules (PTs). However, the impact of angiotensin-converting enzyme type 2 (ACE2) on this process remains uncertain. Overexpressing ACE2 in HEK-293 promotes a selective increase in receptor-mediated albumin endocytosis, without changes in fluid-phase endocytosis. This effect was correlated with increased albumin cell surface binding and increased megalin expression. Treatment with ACE2 inhibitor MLN-4760 blocked the increase in albumin endocytosis induced by ACE2 overexpression in an angiotensin II (Ang II) / AT1R dependent manner. These results were confirmed in LLC-PK1 cells. Using a murine albumin overload model, we observed that proteinuria and reduced PT albumin reabsorption was correlated with lower ACE2 protein expression. Using RNA-Seq databases, we verified that low ACE2 expression correlated with proteinuria in patients with kidney disease. Our results indicate that ACE2 decreases the Ang II/AT1R pathway and increases megalin expression, which in turn enhances PT albumin transport. This pathway is altered in experimental models and patients with kidney diseases. KEY POINTS: ACE2 overexpression increases PT albumin transport. ACE2 overexpression increases megalin expression. ACE2 increases albumin transport by decreasing Ang II / AT1R signalling. Akt activation mediates the increased albumin transport induced by ACE2. Decreased ACE2 expression correlates with proteinuria in mouse models and patients.