The dual role of FcRn in proximal tubule: interaction with megalin for optimal albumin trafficking and maintenance of cellular homeostasis
The renal proximal tubule plays a crucial role in albumin reclamation. FcRn is involved in this process, as it is responsible for intracellular trafficking and recycling of albumin back into circulation via transcytosis. The pattern of interaction between FcRn and megalin during clathrin-mediated endocytosis, which represents the early event of albumin transcytosis, was investigated. Both receptors tend to colocalize in different endocytic vesicles, as their colocalization was increased upon endocytosis induction using megalin ligands, albumin, and b-lactoglobulin, while it was reduced when ovalbumin, a non-megalin ligand, was used. Furthermore, FcRn showed an evident physical interaction with megalin extracellular domain, located outside of ligand binding region. By shedding light on proximal tubule susceptibility to metabolic disorders, such as diabetes mellitus, we found that FcRn expression was reduced in type 1 and type 2 diabetic mice. Since uncontrolled diabetes can lead to diabetic nephropathy, which is considered as a leading cause of end-stage renal disease, the contribution of FcRn absence in the disease progression was questioned. FcRn knocked out (FcRn-/-) mice and BN16 cell models were used for further analysis to investigate relevant morphological and physiological changes, in addition to fundamental cellular processes and signaling pathways. 15-month-old FcRn-/- mice showed a reduction in renal cortices, accompanied by decreased cellular proliferation rate and endocytosis capacity of proximal tubule cells. FcRn deletion was also responsible for cellular homeostasis disruption, represented by enhanced autophagic flux and lysosomal biogenesis, along with increased ATP production. Despite the enhanced autophagy, mTOR pathway was also activated in FcRn-deficient cells, which was concomitant with upregulated amino acid transporters.
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