(Pro)renin receptor activation increases profibrotic markers and fibroblast-like phenotype through MAPK-dependent ROS formation in mouse renal collecting duct cells

ALEXIS ANTONIO GONZALEZ PARRA, Leonardo Zamora, Cristian Reyes-Martinez, Nicolas Salinas-Parra, Nicole Roldan, Catherina A. Cuevas, Stefanny Figueroa, Alex Gonzalez-Vergara, Minolfa C. Prieto

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1134-1144
Number of pages11
JournalClinical and Experimental Pharmacology and Physiology
Volume44
Issue number11
DOIs
StatePublished - 1 Nov 2017

Keywords

  • collecting duct rennin
  • fibrosis
  • intrarenal renin-angiotensin system
  • prorenin receptor
  • reactive oxygen species

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