Prorenin Receptor Activation Increases Profibrotic Markers And Fibroblast Like Phenotype Through Mapk-Dependent Ros Formation In Mouse Renal Collecting Duct Cells

Binding of prorenin or renin to (pro)renin receptor (PRR) activates mitogen activated protein kinases (MAPK)/extracellular regulated kinases 1/2 (ERK 1/2), which have been proposed as mediators in tissue damage. Prorenin, renin, and PRR are overexpressed in the collecting duct (CD) in diabetes and hypertension. Activation of the PRR upregulates profibrotic markers through reactive oxygen species (ROS) formation; however, the exact mechanisms have not been established. We hypothesized that the activation of PRR increases the expression of profibrotic markers through MAPK-dependent ROS formation in CD cells. To address this hypothesis, a mouse renal CD cell line (M-1) was treated with recombinant prorenin plus ROS or MAPK inhibitor to evaluate their effect on the expression of profibrotic markers. Recombinant prorenin increased ROS formation and expression of alpha smooth muscle actin (α-SMA), connecting tissue growth factor (CTGF) and plasminogen activator inhibitor-1 (PAI-1). Induction of profibrotic factors was blunted by antioxidant p-coumaric acid, and partially prevented by lyophilic antioxidant trolox C or ascorbic acid. Inhibition of MAPK pathway (PD98059) prevented the prorenin-dependent ROS formation and augmentation of profibrotic factors, as well as fibroblast-like phenotype. Knockdown of PRR did not show effects on cell viability in M-1 cells and partially reduced the augmentation of fibronectin, collagen I and fibroblast-like phenotype induced by prorenin treatment. These results suggest that the activation of CD-derived PRR plays a role in the development of tubular damage.