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-Golenzer^*^,^,, Michèle Chabert^*^,^,^,**, Pierre Verroust, Jean Chambaz^*^,^,^,**, François-Patrick Châtelet and Athina-Despina Kalopissis¹^,*^,^,

^* Institut National de la Santé et de la Recherche Médicale, U872, Equipe 6, Paris, F-75006 France
Université Pierre et Marie Curie-Paris 6, UMR S 872, Equipe 6, Paris, F-75006, France
Centre de Recherche des Cordeliers, Université Paris Descartes, UMR S 872, Equipe 6, Paris, F-75006, France
^** Ecole Pratique des Hautes Etudes, Laboratoire de Pharmacologie Cellulaire et Moléculaire, Paris, F-75006, France
Institut National de la Santé et de la Recherche Médicale, U538, CHU Saint Antoine, Paris, F-75012, France

Published, JLR Papers in Press, July 24, 2007.

^¹ To whom correspondence should be addressed. e-mail: athina.kalopissis{at}crc.jussieu.fr

We investigated in vivo catabolism of apolipoprotein A-II (apoA-II), a major determinant of plasma HDL levels. Like apoA-I,murine apoA-II (mapoA-II) and human apoA-II (hapoA-II) werereabsorbed in the first segment of kidney proximal tubules ofcontrol and hapoA-II-transgenic mice, respectively. ApoA-IIcolocalized in brush border membranes with cubilin and megalin(the apoA-I receptor and coreceptor, respectively), with mapoA-Iin intracellular vesicles of tubular epithelial cells, and wastargeted to lysosomes, suggestive of degradation. By use ofthree transgenic lines with plasma hapoA-II concentrations rangingfrom normal to three times higher, we established an associationbetween plasma concentration and renal catabolism of hapoA-II.HapoA-II was rapidly internalized in yolk sac epithelial cellsexpressing high levels of cubilin and megalin, colocalized withcubilin and megalin on the cell surface, and effectively competedwith apoA-I for uptake, which was inhibitable by anti-cubilinantibodies. Kidney cortical cells that only express megalininternalized LDL but not apoA-II, apoA-I, or HDL, suggestingthat megalin is not an apoA-II receptor. We show that apoA-IIis efficiently reabsorbed in kidney proximal tubules in relationto its plasma concentration.

Supplementary key words high density lipoprotein • cubilin • megalin • proximal tubule • yolk sac cells • mouse kidney cortical cells • transgenic mice

Abbreviations: AMN, amnionless; apoA-II, apolipoprotein A-II; BN, brown Norwegian; DAB, diaminobenzidine; DiI, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine; hapoA-II, human apolipoprotein A-II; IF, intrinsic factor; IOD, integrated optical density; mapoA-II, murine apolipoprotein A-II; MKC cells, mouse kidney cortical cells; PFA, paraformaldehyde; SR-BI, scavenger receptor class B type I

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