["The Journal of Physiology, EarlyView. ", "\nAbstract figure legend In physiological conditions, angiotensin‐converting enzyme 2 (ACE2) cleaves angiotensin II (Ang II) and decreases angiotensin receptor type 1 (AT1R) signalling. This maintains Akt pathway activation, megalin expression and albumin transport and processing in proximal tubule cells. In disease states such as in albumin overload, ACE2 expression is decreased, which enhances Ang II / AT1R signalling. This activation leads to Akt inhibition, lower megalin expression and subsequent albumin transport and processing in proximal tubules, a mechanism that might influence proteinuria in this state.\n\n\n\n\n\n\n\n\n\nAbstract\nProximal 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.\n\n\n\n\n\n\n\n\n\nKey points\n\nACE2 overexpression increases PT albumin transport.\nACE2 overexpression increases megalin expression.\nACE2 increases albumin transport by decreasing Ang II / AT1R signalling.\nAkt activation mediates the increased albumin transport induced by ACE2.\nDecreased ACE2 expression correlates with proteinuria in mouse models and patients.\n\n\n"]