Acidic organelles mediate TGF-β1-induced cellular fibrosis via (pro)renin receptor and vacuolar ATPase trafficking in human peritoneal mesothelial cells

Ikuko Oba-Yabana (1) , Takefumi Mori (1) , Chika Takahashi (1) , Takuo Hirose (2, 1) , Yusuke Ohsaki (1) , Satoshi Kinugasa (1) , Yoshikazu Muroya (1) , Emiko Sato (1) , Geneviève Nguyen (2) , Rémi Piedagnel (3, 4) , Pierre M Ronco (3, 4) , Kazuhito Totsune (1) , Sadayoshi Ito (1)

1 Tohoku University [Sendai]
2 CIRB - Centre interdisciplinaire de recherche en biologie
3 Des Maladies Rénales Rares aux Maladies Fréquentes, Remodelage et Réparation
4 CHU Tenon [AP-HP]

TGF-β1, which can cause renal tubular injury through a vacuolar-type H+-ATPase (V-ATPase)-mediated pathway, is induced by the glucose degradation product methylglyoxal to yield peritoneal injury and fibrosis. The present study investigated the roles of V-ATPase and its accessory protein, the (pro)renin receptor, in peritoneal fibrosis during peritoneal dialysis. Rats daily administered 20 mM methylglyoxal intraperitoneally developed significant peritoneal fibrosis after 7 days with increased expression of TGF-β and V-ATPase, which was reduced by the inhibition of V-ATPase with co-administration of 100 mM bafilomycin A1. The (pro)renin receptor and V-ATPase were expressed in acidic organelles and cell membranes of human peritoneal mesothelial cells. TGF-β1 upregulated the expression of collagens, α-SMA, and EDA-fibronectin, together with ERK1/2 phosphorylation, which was reduced by inhibition of V-ATPase, (pro)renin receptor, or the MAPK pathway. Fibronectin and the soluble (pro)renin receptor were excreted from cells by acidic organelle trafficking in response to TGF-β1; this excretion was also suppressed by inhibition of V-ATPase. Soluble (pro)renin receptor concentrations in effluents of patients undergoing peritoneal dialysis were associated with the dialysate-to-plasma ratio of creatinine. Together, these results demonstrate a novel fibrosis mechanism through the (pro)renin receptor and V-ATPase in the acidic organelles of peritoneal mesothelial cells.

Domaines: Urologie et Néphrologie; Biochimie, Biologie Moléculaire

Ikuko Oba-Yabana, Takefumi Mori, Chika Takahashi, Takuo Hirose, Yusuke Ohsaki, et al.. Acidic organelles mediate TGF-β1-induced cellular fibrosis via (pro)renin receptor and vacuolar ATPase trafficking in human peritoneal mesothelial cells. Scientific Reports, 2018, 8, pp.2648. ⟨10.1038/s41598-018-20940-x⟩. ⟨hal-01718069⟩