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Abstract: TH-PO983

The Effect of Sertraline on Reduction of Albuminuria Due to the Inhibition of Caveolae Pathway Through Glomerular Endothelial and Epithelial Cells

Session Information

Category: Pathology and Lab Medicine

  • 1501 Pathology and Lab Medicine: Basic

Authors

  • Moriyama, Takahito, Tokyo Women's Medical University, Tokyo, Japan
  • Nitta, Kosaku, Tokyo Women's Medical University, Tokyo, Japan
Background

Previously, we have reported the caveolae mediated endocytosis, transcytosis, and exocytosis of albumin through glomerular endothelial cells as a new etiology of urinary albumin excretion (J Cell Biochem 116; 1065-9: 2015, J Cell Physiol 232; 3565-73: 2017). The selective serotonin reuptake inhibitor, sertraline, inhibited the dynamin which played a pivotal role for fission of caveolae from cell membrane in caveolae endocytosis. We hypothesized that sertraline might reduce the albuminuria by interfere the caveolae mediated intracellular trafficking pathway.

Methods

In this study, we analyzed whether the dynamin inhibitor sertraline interfered the albumin internalization through caveolae in glomerular epithelial and endothelial cells, and sertraline reduced the amount of albuminuria in puromycin aminonucleoside induced nephrotic syndrome modeled mice (PAN mice) as a novel treatment of glomerulonephritis.

Results

In vitro studies, western blotting analysis and immunofluorescence (IF) study showed that dose dependent (5 and 10 µM) treatment of sertraline significantly reduced the expression of albumin in glomerular endothelial and epithelial cells (P<0.01), though the Caveolin-1 (Cav-1) expression was not reduced. In vivo analysis, the electron microscopic findings showed that the foot process fusion and swelling of endothelial cells in dimethyl sulfoxide (DMSO) treated PAN mice as vehicle and also sertraline treated PAN mice, and the IF analysis showed the stronger Cav-1 expression on capillaries in both mice in comparison to normal control mice (P<0.0001). However, the amount of proteinuria was not increased in sertraline treated PAN mice in comparison to normal control mice (0.05 vs. 0.02 mg/mgCre, p=0.17), though it was significantly increased in DMSO treated PAN mice (0.12 vs. 0.02 mg/mgCre, P=0.0027).

Conclusion

Though the foot process fusion, endothelial swelling, and caveolin-1 expressions were occurred, albumin internalization into glomerular endothelial and epithelial cells and albuminuria in PAN mice were reduced by sertraline. These results indicated that sertraline interfered albumin internalization thorough caveolae by inhibition of dynamin and resulted in reduction of albuminuria. Sertraline might become the novel therapeutic option to reduce albuminuria in glomerulonephritis.