Receptor-associated protein is important for normal processing of megalin in kidney proximal tubules

Citation
H. Birn et al., Receptor-associated protein is important for normal processing of megalin in kidney proximal tubules, J AM S NEPH, 11(2), 2000, pp. 191-202
Citations number
54
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Urology & Nephrology","da verificare
Journal title
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
ISSN journal
1046-6673 → ACNP
Volume
11
Issue
2
Year of publication
2000
Pages
191 - 202
Database
ISI
SICI code
1046-6673(200002)11:2<191:RPIIFN>2.0.ZU;2-Q
Abstract
The receptor-associated protein (RAP) has been identified as a chaperone re gulating the expression and processing of the LDL receptor-related protein. RAP also binds to the related 600-kD multiligand endocytic receptor megali n expressed in many absorptive epithelia including renal proximal tubule. T he present study examines the effect of RAP gene disruption on megalin expr ession and subcellular distribution in the proximal tubule as well as the e ffect on tubular protein reabsorption. It is shown that RAP is important fo r the normal expression and function of megalin. Megalin expression was red uced to approximately 23% estimated by immunoblotting and supported by immu nocytochemistry and by the amount of megalin recovered by RAP affinity chro matography. Light- and electron microscope immunocytochemistry as well as a nalyses on separated membrane fractions showed significant changes in the s ubcellular distribution of megalin. A significant reduction in the normal b rush border labeling was observed in association with increased labeling of rough endoplasmic reticulum and the smooth paramembranous endoplasmic reti culum along the basolateral membranes. RAP deficiency was associated with c hanges in urinary protein composition, enabling the identification of alpha -amylase as a new ligand for megalin. In addition, an increased excretion o f vitamin D-binding protein, a recently identified ligand to megalin, was o bserved supporting changes in tubular protein reabsorption. The present dat a show that RAP is of crucial importance for normal processing and function of megalin, suggesting a chaperone-like function of this protein in the ki dney proximal tubule.