Apolipoprotein A-II is catabolized in the kidney as a function of its plasma concentration

Sonia Dugué-Pujol, Xavier Rousset, Danielle Château, Danièle Pastier, Christophe Klein, Jeannine Demeurie, Charlotte Cywiner-Golentzer, Michèle Chabert, Pierre Verroust, Jean Chambaz, François Patrick Châtelet, and Athina Despina Kalopissis

INSERM U872; Université Pierre et Marie Curie-Paris 6, UMR S 872; Centre de Recherche des Cordeliers, Université Paris Descartes, UMR S 872; EPHE, Laboratoire de Pharmacologie Cellulaire et Moléculaire, Centre de Recherche des Cordeliers, Paris 75006

Corresponding Author: athina.kalopissis-u505{at}bhdc.jussieu.fr

We investigated in vivo catabolism of apolipoprotein (apo) A-II, a major determinant of plasma HDL levels. Like apo A-I, murine apo A-II (mapo A-II) and human apo A-II (hapo A-II) were reabsorbed in the first segment of kidney proximal tubules of control and hapo A-II transgenic mice, respectively. Apo A-II colocalized in brush border membranes with cubilin and megalin (the apo A-I receptor and coreceptor, respectively), with murine apo A-I in intracellular vesicles of tubular epithelial cells, and was targeted to lysosomes, suggestive of degradation. By use of three transgenic lines with plasma hapo A-II concentrations ranging from normal to 3 times higher we established an association between plasma concentration and renal catabolism of hapo A-II. Hapo A-II was rapidly internalized in yolk sac epithelial cells expressing high levels of cubilin and megalin, colocalized with cubilin and megalin on the cell surface, and effectively competed with apo A-I for uptake, which was inhibitable by anticubilin antibodies. Kidney cortical cells that only express megalin, internalized LDL but not apo A-II, apo A-I or HDL, suggesting that megalin is not an apo A-II receptor. We show that apo A-II is efficiently reabsorbed in kidney proximal tubules in relation to its plasma concentration.

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