Glomerular protein sieving and implications for renal failure in Fanconi syndrome

Abstract

To our knowledge, this study provides the first estimates of human in vivo GSCs. Our model explains why tubular proteinuria of Fanconi syndrome includes proteins of mass of albumin and above as well as low-molecular-weight proteins, and further characterizes the endocytic pathway(s) believed defective in these syndromes. High urinary concentrations of potentially bioactive hormones such as PTH, insulin, IGF-1 and the chemokine monocyte chemoattractant protein-1 (MCP-1), were found; their presence in tubular fluid may contribute to the hypercalciuria, interstitial fibrosis, and the progressive renal failure of Fanconi syndromes.

Megalin-dependent cubilin-mediated endocytosis is a major pathway for the apical uptake of transferrin in polarized epithelia

“…The apparent high filtration of Tf is remarkable because the size of this protein (80 kDa) is close to the suggested size cut-off value (80-100 kDa) of proteins permeable in the glomeruli (31). However, filtration of Tf is also indicated in a recent study (32) showing Tf as an abundant protein in urine of patients with deficient renal, tubular protein reabsorption.…”

Lipocalin-2 (24p3/Neutrophil Gelatinase-associated Lipocalin (NGAL)) Receptor Is Expressed in Distal Nephron and Mediates Protein Endocytosis

“…5 Besides its established function as a receptor for lipocalin-2/ NGAL/24p3 (30,31), a putative role of 24p3R in RME of (metalbinding) proteins was tested with a focus on the putative ligands MT, Tf, and albumin based on the following rationale. (i) These proteins bind metals, such as iron, zinc, or cadmium, but also calcium (17, 50 -52); (ii) they are filtered by the kidney glomeruli (17,53); and (iii) they are ligands of the megalin-cubilinamnionless receptor complex in the PT (4).…”

“…MT with a K D of ϳ100 M (18)) or due to exhaustion of the reabsorptive capacity of the system (e.g. following glomerular or PT damage and ensuing proteinuria) (6,13,14,53). A high-affinity protein reabsorption system in the distal nephron, as suggested by the present study, could contribute to exhaustive protein reabsorption by the nephron under physiological conditions, as deduced from previous micropuncture studies, or limit protein losses associated with renal diseases, including various forms of inherited or acquired Fanconi syndrome (53).…”

Renal Iron Metabolism

“…In normal urine, the quantity of Tf is approximately 0.32 to 0.47 mg/24 h (12), but in Fanconi syndrome, a disease that is characterized by generalized dysfunction of renal proximal tubules, urinary concentrations of Tf increase markedly (13). These findings undermine the commonly held belief that the high molecular weight of Tf prevents it from being filtered by the glomerulus (14).…”