Surface megalin expression is a target to the inhibitory effect of bradykinin on the renal albumin endocytosis

• Published in: Peptides (New York, N.Y. : 1980) N.Y. : 1980), 2021-12, Vol.146, p.170646-170646, Article 170646
• Main Authors: Alves, Sarah A.S., Florentino, Lucas S., Teixeira, Douglas E., Silva-Aguiar, Rodrigo P., Peruchetti, Diogo B., Oliveira, Ana Carolina, Scharfstein, Julio, Marzolo, María-Paz, Pinheiro, Ana Acacia S., Caruso-Neves, Celso
• Format: Article
• Language: English
• Subjects: Albumins - metabolism; Albuminuria; Animals; Bradykinin; Bradykinin - pharmacology; Cell Line; Endocytosis; Endocytosis - drug effects; Enzyme Activation; G protein‐coupled receptor; Kidney; Kidney Tubules, Proximal - drug effects; Kidney Tubules, Proximal - metabolism; LLC-PK1 Cells; Low Density Lipoprotein Receptor-Related Protein-2 - metabolism; Protein kinase C; Protein Kinase C - metabolism; Receptor, Bradykinin B2 - metabolism; Swine
• ISSN: 0196-9781; 1873-5169
• DOI: 10.1016/j.peptides.2021.170646

[Display omitted] •Bradykinin inhibits megalin-mediated albumin endocytosis in proximal tubule cells.•B2 receptor mediates the inhibition of albumin endocytosis by bradykinin.•PKC is the central molecule involved in the inhibitory effects of bradykinin.•Bradykinin stalls megalin in EEA1+ endosomes in proximal tubule cells.•Surface megalin expression is reduced by bradykinin in proximal tubule cells. Megalin-mediated albumin endocytosis plays a critical role in albumin reabsorption in proximal tubule (PT) epithelial cells (PTECs). Some studies have pointed out the modulatory effect of bradykinin (BK) on urinary protein excretion, but its role in PT protein endocytosis has not yet been determined. Here, we studied the possible correlation between BK and albumin endocytosis in PT. Using LLC-PK1 cells, a model of PTECs, we showed that BK specifically inhibited megalin-mediated albumin endocytosis. This inhibitory effect of BK was mediated by B2 receptor (B2R) because it was abolished by HOE140, an antagonist of B2R, but it was not affected by Lys-des-Arg9-BK, an antagonist of B1. BK induced the stall of megalin in EEA1+ endosomes, but not in LAMP1+ lysosomes, leading to a decrease in surface megalin expression. In addition, we showed that BK, through B2R, activated calphostin C-sensitive protein kinase C, which mediated its effect on the surface megalin expression and albumin endocytosis. These results reveal an important modulatory mechanism of PT albumin endocytosis by BK, which opens new possibilities to understanding the effect of BK on urinary albumin excretion.