Albumin Expands Albumin Reabsorption Capacity in Proximal Tubule Epithelial Cells through a Positive Feedback Loop between AKT and Megalin

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dc.contributor.authorSilva-Aguiar, Rodrigo P.
dc.contributor.authorPeruchetti, Diogo B.
dc.contributor.authorFlorentino, Lucas S.
dc.contributor.authorTakiya, Christina M.
dc.contributor.authorMarzolo, Maria-Paz
dc.contributor.authorDias, Wagner B.
dc.contributor.authorPinheiro, Ana Acacia S.
dc.contributor.authorCaruso-Neves, Celso
dc.date.accessioned2025-01-20T22:00:43Z
dc.date.available2025-01-20T22:00:43Z
dc.date.issued2022
dc.description.abstractRenal proximal tubule cells (PTECs) act as urine gatekeepers, constantly and efficiently avoiding urinary protein waste through receptor-mediated endocytosis. Despite its importance, little is known about how this process is modulated in physiologic conditions. Data suggest that the phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT) pathway regulates PTEC protein reabsorption. Here, we worked on the hypothesis that the physiologic albumin concentration and PI3K/AKT pathway form a positive feedback loop to expand endocytic capacity. Using LLC-PK1 cells, a model of PTECs, we showed that the PI3K/AKT pathway is required for megalin recycling and surface expression, affecting albumin uptake. Inhibition of this pathway stalls megalin at EEA1(+) endosomes. Physiologic albumin concentration (0.01 mg/mL) activated AKT; this depends on megalin-mediated albumin endocytosis and requires previous activation of PI3K/mTORC2. This effect is correlated to the increase in albumin endocytosis, a phenomenon that we refer to as "albumin-induced albumin endocytosis". Mice treated with L-lysine present decreased albumin endocytosis leading to proteinuria and albuminuria associated with inhibition of AKT activity. Renal cortex explants obtained from control mice treated with MK-2206 decreased albumin uptake and promoted megalin internalization. Our data highlight the mechanism behind the capacity of PTECs to adapt albumin reabsorption to physiologic fluctuations in its filtration, avoiding urinary excretion.
dc.fuente.origenWOS
dc.identifier.doi10.3390/ijms23020848
dc.identifier.eissn1422-0067
dc.identifier.urihttps://doi.org/10.3390/ijms23020848
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/93742
dc.identifier.wosidWOS:000750559400001
dc.issue.numero2
dc.language.isoen
dc.revistaInternational journal of molecular sciences
dc.rightsacceso restringido
dc.subjectalbumin endocytosis
dc.subjectAKT
dc.subjectPKB
dc.subjectmegalin
dc.subjectproximal tubule
dc.subjectendosome signaling
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleAlbumin Expands Albumin Reabsorption Capacity in Proximal Tubule Epithelial Cells through a Positive Feedback Loop between AKT and Megalin
dc.typeartículo
dc.volumen23
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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