Recent studies suggested that activation of the PRR upregulates profibrotic markers through reactive oxygen species (ROS) formation; however, the exact mechanisms have not been investigated in CD cells. We hypothesized that activation of the PRR increases the expression of profibrotic markers through MAPK‐dependent ROS formation in CD cells. Mouse renal CD cell line (M‐1) was treated with recombinant prorenin plus ROS or MAPK inhibitors and PRR‐shRNA to evaluate their effect on the expression of profibrotic markers. PRR immunostaining revealed plasma membrane and intracellular localization. Recombinant prorenin increases ROS formation (6.0 ± 0.5 vs 3.9 ± 0.1 nmol/L DCF/μg total protein, P < .05) and expression of profibrotic markers CTGF (149 ± 12%, P < .05), α‐SMA (160 ± 20%, P < .05), and PAI‐I (153 ± 13%, P < .05) at 10−8 mol/L. Recombinant prorenin‐induced phospho ERK 1/2 (p44 and p42) at 10−8 and 10−6 mol/L after 20 minutes. Prorenin‐dependent ROS formation and augmentation of profibrotic factors were blunted by ROS scavengers (trolox, p‐coumaric acid, ascorbic acid), the MEK inhibitor PD98059 and PRR transfections with PRR‐shRNA. No effects were observed in the presence of antioxidants alone. Prorenin‐induced upregulation of collagen I and fibronectin was blunted by ROS scavenging or MEK inhibition independently. PRR‐shRNA partially prevented this induction. After 24 hours prorenin treatment M‐1 cells undergo to epithelial–mesenchymal transition phenotype, however MEK inhibitor PD98059 and PRR knockdown prevented this effect. These results suggest that PRR might have a significant role in tubular damage during conditions of high prorenin‐renin secretion in the CD.