Receptor-Mediated Endocytosis in the Proximal Tubule

Abstract

Cells lining the proximal tubule (PT) of the kidney are highly specialized for apical endocytosis of filtered proteins and small bioactive molecules from the glomerular ultrafiltrate to maintain essentially protein-free urine. Compromise of this pathway results in low molecular weight (LMW) proteinuria that can progress to end-stage kidney disease. This review describes our current understanding of the endocytic pathway and the multiligand receptors that mediate LMW protein uptake in PT cells, how these are regulated in response to physiologic cues, and the molecular basis of inherited diseases characterized by LMW proteinuria.

Keywords: Dent disease; Lowe syndrome; albumin; apical; cubilin; cystinosis; kidney; megalin; proteinuria.

Figure 1

Multiligand receptors in the proximal tubule. Megalin and cubilin regulate the uptake of low molecular weight proteins from the glomerular filtrate. The cytoplasmic tail of megalin contains two NPXY motifs that bind to the Dab2 clathrin adaptor protein as well as a related NQNY sequence implicated in apical delivery. Megalin/cubilin ligands that are filtered through the glomerular barrier are listed in Table 1. Abbreviations: CUB, compliment C1r/C1s, Uegf, Bmp1; Dab2, Disabled-2 protein; EGF, epidermal growth factor.

Figure 2

The apical endocytic pathway in MDCK and PT cells. (a) Cargo internalized from the apical and basolateral surface of MDCK cells via clathrin-coated pits enters Rab5-positive AEEs and BEEs, respectively. Most proteins return to the plasma membrane from these compartments via a Rab4-dependent fast recycling pathway, but they may also be delivered to Rab11-positive AREs or Rab8-positive CREs. Ligands released from internalized receptors in acidified early endosomes are transported to Rab7-positive MVBs and eventually to lysosomes. (b) In PT cells, apical proteins are internalized in irregular clathrin-coated invaginations into apical early endosomes that fuse to form larger AVs. Recycling of membrane proteins can occur from AEEs or AVs via DATs, whereas soluble components of AVs are delivered to lysosomes. The Rab proteins and other machinery associated with these compartments remain largely unknown. Abbreviations: AEE, apical early endosomes; ARE, apical recycling endosomes; AV, apical vacuole; BEE, basolateral early endosomes; CRE, common recycling endosomes; DAT, dense apical tubules; MDCK, Madin-Darby canine kidney; MVB, multivesicular bodies; PT, proximal tubule.