Megalin Is Predominantly Observed in Vesicular Structures in First and Third Trimester Cytotrophoblasts of the Human Placenta

Abstract

SummaryThe membrane receptor megalin is crucial for normal fetal development. Besides its expression in the developing fetus, megalin is also expressed in the human placenta. Similar to its established function in the kidney proximal tubules, placental megalin has been proposed to mediate uptake of vital nutrients. However, details of megalin expression, subcellular localization, and function in the human placenta remain to be established. By immunohistochemical analyses of first trimester and term human placenta, we showed that megalin is predominantly expressed in cytotrophoblasts, the highly proliferative cells in placenta. Only limited amounts of megalin could be detected in syncytiotrophoblasts and least in term placenta syncytiotrophoblasts. Immunocytochemical analyses furthermore showed that placental megalin associates with structures of the endolysosomal apparatus. Combined, our results clearly place placental megalin in the context of endocytosis and trafficking of ligands. However, due to the limited expression of megalin in syncytiotrophoblasts, especially in term placenta, it appears that the main role for placental megalin is not to mediate uptake of nutrients from the maternal bloodstream, as previously proposed. In contrast, our results point toward novel and complex functions for megalin in the cytotrophoblasts. Thus, we propose that the perception of placental megalin localization and function should be revised. (J Histochem Cytochem 64:769-784, 2016)

The Neonatal Fc Receptor (FcRn): A Misnomer?

“…It is still unknown why albumin and IgG are transported differently, but involvement of other albumin receptors could be part of the explanation. For example, megalin and cubilin (Box 4) have been found to be expressed in the placenta (159–161), and it has been suggested that they might facilitate retrograde recycling of albumin back to the maternal circulation (159).…”

Cadmium Handling, Toxicity and Molecular Targets Involved during Pregnancy: Lessons from Experimental Models

“…This Cd redistribution could be explained by MT redistribution, since they observed the same pattern with MT levels during this time of gestation [ 47 , 64 ]. Placenta has been showed to highly express megalin in cytotrophoblasts during first and third trimester [ 65 ]: megalin is a transmembrane receptor which mediates uptake and trafficking of many ligands including MT in kidney and other tissues [ 66 , 67 , 68 ]. However, other transporters that participate in receptor-mediated endocytosis of MT could be also involved [ 69 , 70 ].…”

“…Using in vivo models, Cd exposure has been associated to preeclampsia development with increased systolic pressure and proteinuria [ 72 , 73 , 74 ]. The mechanisms suggested for preeclampsia induction by Cd exposure are: placental damage caused by oxidative DNA damage [ 65 , 72 ], and high levels of corticosterone in plasma, consequence of placental alterations (downregulation of 11β-hydroxysteroid dehydrogenase, 11β-HSD2) [ 73 , 75 ]. Other mechanisms possibly related to the development of preeclampsia are immunological disorders.…”

“…Similarly to TRPV6, it is possible that the membrane receptor megalin plays a role in Cd transfer. Megalin is known to participate in the reabsorption of the Cd-MT complex in proximal tubules [ 66 ] and it is present in cytotrophoblasts as well as syncytiotrophoblasts of human [ 65 ] and mice placenta [ 101 ] where it is thought to contribute to the transfer of nutrients to the fetus. So it is plausible that this receptor mediates, to some extent, Cd endocytosis and subsequent transport across the placenta; nevertheless, this speculation needs to be confirmed by experimental studies.…”

Selective Ablation of Megalin in the Retinal Pigment Epithelium Results in Megaophthalmos, Macromelanosome Formation and Severe Retina Degeneration

“…Here, megalin mediates reabsorption of filtered plasma proteins, rescuing vital nutrients from urinary excretion 7. Besides the kidney, megalin is also expressed in a number of other specialized epithelia throughout the body including type II pneumocytes of the lung, the choroid plexus epithelium, and placental cytotrophoblasts 8–11. Notably, megalin is also expressed in the non-pigmented ciliary body epithelium as well as the RPE in the adult mammalian eye 10,12,13…”