Mouse model of proximal tubule endocytic dysfunction

Abstract

We report here the efficient genetic ablation of megalin, cubilin or both, using a Cre transgene driven by the Wnt4 promoter. The viable megalin/cubilin double-deficient mice now allow for detailed large-scale group analysis, and we anticipate that the mice will be of great value as an animal model for proximal tubulopathies with disrupted endocytosis.

Time Course of Pathogenic and Adaptation Mechanisms in Cystinotic Mouse Kidneys

“…21 PTCs are specialized to capture ultrafiltrated proteins by apical receptor-mediated endocytosis (ARME) through abundantly expressed, rapidly recycling multiligand tandem receptors, megalin, and cubilin. 22 Megalin-and cubilin-knockout mice show defective PTC endocytosis and urinary loss of ultrafitrated plasma proteins [23][24][25][26] and lysosomal enzymes. 27,28 Although defective ARME caused by loss of megalin/cubilin was a possible explanation for proteinuria of cystinotic patients, normal immunolabeling of megalin/cubilin was reported in an end stage cystinotic kidney despite massive proteinuria, calling attention to glomerular leakage.…”

Is the Albumin Retrieval Hypothesis a Paradigm Shift for Nephrology?

“…They have used the mouse and their own elegant transgenic models of conditional megalin and cubilin, or megalin only null mice. 4 Curiously, Weyer et al do not address the question of whether there are indeed significant quantities of such degraded albumin fragments in mouse urine or their nature; in fact, the molecular identities and quantities of these fragments are still unknown in any species.The reliability of the measurements reported in at least one of the references cited in support of the existence of large quantities of albumin fragments in human urine has been questioned. 5,6 However, in their current paper, the Aårhus group propose that the origins of these albumin fragments, if they are really generated by the kidney, must depend on the integrity of the megalin-cubilin pathway.…”

“…They have used the mouse and their own elegant transgenic models of conditional megalin and cubilin, or megalin only null mice. 4 Curiously, Weyer et al do not address the question of whether there are indeed significant quantities of such degraded albumin fragments in mouse urine or their nature; in fact, the molecular identities and quantities of these fragments are still unknown in any species.…”

“…5,6 However, in their current paper, the Aårhus group propose that the origins of these albumin fragments, if they are really generated by the kidney, must depend on the integrity of the megalin-cubilin pathway. 4 This pathway appears to be the dominant albumin transporter and uptake mechanism in the proximal tubule, and if this is true, the null mice should not have any albumin fragments in their urine. As it happens, the urine of these mice did contain albumin fragments, at least of its radiolabeled form, and the interpretation of this is that they are prerenal in origin-generated in the circulating plasma and filtered-because a postrenal source seems unlikely.…”

“…Although in the nocturnal FHN arm, the delivered dialysis dose was profoundly higher than in the short FHN arm, there was no effect on the same predefined primary outcome parameters. 4 The nocturnal FHN arm suffered from a slow and difficult recruiting process, which allowed only 87 patients to be randomized and thus may be considered severely underpowered. 5 Because the FHN nocturnal study was not able to give the desired final answer on dialysis dosing, the book on nocturnal HD is not closed.…”