Treatment combining aliskiren with paricalcitol is effective against progressive renal tubulointerstitial fibrosis via dual blockade of intrarenal renin

PLoS One. 2017 Jul 28;12(7):e0181757. doi: 10.1371/journal.pone.0181757. eCollection 2017.

Abstract

The aim of this study was to assess any potential additive effects of a treatment combining aliskiren with paricalcitol on reducing renal fibrosis. C57BL/6J mice were treated individually with aliskiren and/or paricalcitol until 7 days after initiation of unilateral ureteral obstruction (UUO).In obstructed kidneys of UUO mice, monotherapy with aliskiren or paricalcitol significantly attenuated interstitial fibrosis, collagen IV accumulation, and α-smooth muscle actin- and terminal deoxynucleotidyl transferase-mediated biotin nick end-labeling-positive cells. The combination treatment showed additive efficacy in inhibition of these parameters. Renal NADPH oxidase (Nox)1 and Nox2 were significantly decreased by aliskiren or paricalcitol alone or in combination, while renal Nox4 expression was significantly reduced by paricalcitol mono- or combination treatment. Increased levels of p-Erk and p-p38 MAPK, and NF-κB in UUO kidneys were also significantly reduced by either aliskiren or paricalcitol treatment alone or in combination. Aliskiren or paricalcitol monotherapy significantly reduced the expression of (pro)renin receptor in UUO kidneys. In addition, aliskiren tended to augment renin expression in UUO kidneys, but paricalcitol reduced its expression level. The combination treatment effectively blocked both (pro)renin receptor and renin expression induced by aliskiren, and resulted in a further reduction of the renal expression of angiotensin II AT1 receptor. Aliskiren failed to increase the expression of vitamin D receptor in UUO kidneys, but the combination treatment restored its expression level. Taken together, a treatment combining aliskiren with paricalcitol better inhibits UUO-induced renal injury. The mechanism of this synergy may involve more profound inhibition of the intrarenal renin-angiotensin system.

MeSH terms

  • Amides / pharmacology
  • Amides / therapeutic use*
  • Animals
  • Apoptosis / drug effects
  • Collagen Type IV / metabolism
  • Disease Progression*
  • Drug Therapy, Combination
  • Ergocalciferols / pharmacology
  • Ergocalciferols / therapeutic use*
  • Fibrosis
  • Fumarates / pharmacology
  • Fumarates / therapeutic use*
  • Inflammation Mediators / metabolism
  • Kidney / metabolism*
  • Kidney Diseases / drug therapy*
  • Kidney Diseases / pathology
  • Male
  • Mice, Inbred C57BL
  • Myofibroblasts / drug effects
  • Myofibroblasts / metabolism
  • Oxidative Stress / drug effects
  • Receptors, Calcitriol / metabolism
  • Renin / metabolism*
  • Renin-Angiotensin System / drug effects
  • Treatment Outcome
  • Ureteral Obstruction / drug therapy
  • Ureteral Obstruction / pathology

Substances

  • Amides
  • Collagen Type IV
  • Ergocalciferols
  • Fumarates
  • Inflammation Mediators
  • Receptors, Calcitriol
  • aliskiren
  • paricalcitol
  • Renin

Grants and funding

This research was supported by the Basic Science Research Program through the National Research Foundation (NRF) of Korea funded by the Ministry of Science, ICT & Future Planning, Republic of Korea (NRF-2015R1C1A1A02037258). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.