Endocytic adaptation to functional demand by the kidney proximal tubule. (16th June 2021)

• Record Type: Journal Article
• Authors: Weisz, Ora A.
• Is Part Of: Journal of physiology. Volume 599:Number 14(2021)
• Page Start: 3437
• Page End: 3446
• Publication Date: 2021-06-16
• Subjects: albumin -- cubilin -- endocytosis -- glomerular filtration rate -- megalin -- proteinuria; Physiology -- Periodicals; 612.005
• DOI: 10.1113/JP281599
• Languages: English
• ISSNs: 0022-3751

Abstract

Abstract: The kidney proximal tubule (PT) efficiently recovers the low level of albumin and other proteins that normally escape the glomerular filtration barrier. Two large receptors, megalin and cubilin/amnionless (CUBAM), bind to and efficiently retrieve these predominantly low molecular‐weight proteins via clathrin‐mediated endocytosis. Studies in cell culture models suggest that PT cells may sense changes in shear stress to modulate recovery of filtered proteins in response to normal variations in filtration rate. Impairments in PT endocytic function lead to the excretion of filtered proteins into the urine (tubular proteinuria). Remarkably, when the glomerular filtration barrier is breached, the PT is able to recover excess albumin with a capacity that is orders of magnitude higher than normal. What mediates this excess capacity for albumin uptake under nephrotic conditions, and why doesn't it compensate to prevent tubular proteinuria? Here we propose an integrated new working model to describe the PT recovery of filtered proteins under normal and nephrotic states. We hypothesize that uptake via the fluid phase provides excess capacity to recover high concentrations of filtered proteins under nephrotic conditions. Further, concentration of tubular fluid along the tubule axis will enhance the efficiency of uptake in more distal regions of the PT. By contrast to cells where fluid phase and receptor‐mediated uptake are independent pathways, expression of megalin is required to maintain apical endocytic pathway integrity and is essential for both uptake mechanisms. This model accounts for both the high‐affinity and the high‐capacity responses to filtration load in physiological and pathological states. Abstract : Abstract figure legend Multiligand receptors on the kidney proximal tubule (PT) efficiently recover the low level of albumin and other proteins that normally escape the glomerular filtration barrier. However, the PT has the capacity to internalize much higher amounts of proteins, as revealed when the glomerular filtration barrier is breached. Data from cell culture and mouse studies suggest a unifying model to explain how the PT handles normal and nephrotic levels of filtered proteins.