Modelling normal and nephrotic axial uptake of albumin and other filtered proteins along the proximal tubule. (2nd March 2022)

• Record Type: Journal Article
• Authors: Edwards, Aurélie; Long, Kimberly R.; Baty, Catherine J.; Shipman, Katherine E.; Weisz, Ora A.
• Is Part Of: Journal of physiology. Volume 600:Number 8(2022)
• Page Start: 1933
• Page End: 1952
• Publication Date: 2022-03-02
• Subjects: cubilin -- endocytosis -- kidney -- megalin -- proteinuria; Physiology -- Periodicals; 612.005
• DOI: 10.1113/JP282885
• Languages: English
• ISSNs: 0022-3751

Abstract

Abstract : Abstract: Recent studies indicate that filtered albumin is retrieved in the proximal tubule (PT) via three pathways: receptor‐mediated endocytosis via cubilin (high affinity) and megalin (low affinity), and fluid‐phase uptake. Expression of megalin is required to maintain all three pathways, making it challenging to determine their respective contributions. Moreover, uptake of filtered molecules varies between the sub‐segments (S1, S2 and S3) that make up the PT. Here we used new and published data to develop a mathematical model that predicts the rates of albumin uptake in mouse PT sub‐segments in normal and nephrotic states, and partially accounts for competition by β2 ‐microglobulin (β2m) and immunoglobulin G (IgG). Our simulations indicate that receptor‐mediated, rather than fluid‐phase, uptake accounts for the vast majority of ligand recovery. Our model predicts that ∼75% of normally filtered albumin is reabsorbed via cubilin; however, megalin‐mediated uptake predominates under nephrotic conditions. Our results also suggest that ∼80% of albumin is normally recovered in S1, whereas nephrotic conditions or knockout of cubilin shifts the bulk of albumin uptake to S2. The model predicts β2m and IgG axial recovery profiles qualitatively similar to those of albumin under normal conditions. In contrast with albumin, however, the bulk of IgG and β2m uptake still occurs in S1 under nephrotic conditions. Overall, our model provides a kinetic rationale for why tubular proteinuria can occur even though a large excess in potential PT uptake capacity exists, and suggests testable predictions to expand our understanding of the recovery profile of filtered proteins along the PT. Key points: We used new and published data to develop a mathematical model that predicts the profile of albumin uptake in the mouse proximal tubule in normal and nephrotic states, and partially accounts for competitive inhibition of uptake by normally filtered and pathological ligands. Three pathways, consisting of high‐affinity uptake by cubilin receptors, low‐affinity uptake by megalin receptors and fluid phase uptake, contribute to the overall retrieval of filtered proteins. The axial profile and efficiency of protein uptake depend on the initial filtrate composition and the individual protein affinities for megalin and cubilin. Under normal conditions, the majority of albumin is retrieved in sub‐segment S1 but shifts to sub‐segment S2 under nephrotic conditions. Other proteins exhibit different uptake profiles. Our model explains how tubular proteinuria can occur despite a large excess in potential proximal tubule uptake capacity. Abstract : Abstract figure legend Data from mouse models and from cultured proximal tubule (PT) cells were used to create a mathematical model that predicts the uptake profile of albumin and other filtered ligands along the mouse PT in normal and nephrotic states. The distinct contributions of cubilin receptors (magenta), megalin receptors (green) and fluid phase uptake (blue) to total albumin retrieval (black) in S1, S2 and S3 sub‐segments of the PT are delineated. Under normal conditions, albumin is primarily recovered in the S1 sub‐segment by cubilin, whereas under nephrotic conditions the majority is retrieved in S2. Other proteins exhibit strikingly different uptake profiles. Our model explains how the distribution and capacity of high‐affinity and low‐affinity uptake pathways enable uptake of albumin over a broad range of filtered concentrations, and how tubular proteinuria can occur despite a large excess in potential PT uptake capacity. Created with BioRender.com