Proteinuria is a prognostic indicator of progressive kidney disease and poor cardiovascular outcomes. Abnormally filtered bioactive macromolecules interact with proximal tubular epithelial cells (PTECs), which results in the development of proteinuric nephropathy. This condition is characterized by alterations in PTEC growth, apoptosis, gene transcription and inflammatory cytokine production as a consequence of dysregulated signaling pathways that are stimulated by proteinuric tubular fluid. The megalin-cubilin complex mediates the uptake of several proteins, including albumin, into PTECs. Megalin might also possess intrinsic signaling properties and the ability to regulate cell signaling pathways and gene transcription after processing regulated intramembrane proteolysis. Megalin could, therefore, link abnormal PTEC albumin exposure with altered growth factor receptor activation, proinflammatory and profibrotic signaling, and gene transcription. Evidence now suggests that other PTEC pathways for protein reabsorption of (patho)physiological importance might be mediated by the neonatal Fc receptor and CD36.