Dihydroquercetin protects against renal fibrosis by activating the Nrf2 pathway

Phytomedicine. 2020 Apr;69:153185. doi: 10.1016/j.phymed.2020.153185. Epub 2020 Feb 19.

Abstract

Background: Dihydroquercetin (DHQ) is an antifibrotic agent. However, whether DHQ can prevent renal fibrosis remains unknown.

Purpose: This study aimed to investigate the effects of DHQ on tubulointerstitial fibrosis and its underlying mechanisms in unilateral ureteral obstruction (UUO) mice in vivo and NRK-49F cells in vitro.

Methods: In vivo, UUO mice received vehicle or DHQ treatment. In vitro, NRK-49F cells were pretreated with DHQ and exposed to transforming growth factor-β1 (TGF-β1). Changes in fibroblast activation, collagen synthesis, oxidative stress, and related signaling pathways were assessed by immunohistochemical staining, Western blot analysis, real-time reverse transcription-PCR, and fluorescence microscopy.

Results: UUO induced tubular atrophy, inflammation, fibroblast differentiation into myofibroblast, and collagen deposition, whereas DHQ ameliorated these effects. UUO also resulted in decreased levels of nuclear factor-erythroid-2-related factor 2 (Nrf2), catalase, and heme oxygenase-1, but increased H2O2 and malondialdehyde levels. DHQ treatment corrected these changes. In vitro, the intracellular Nrf2 level of NRK-49F exposed to TGF-β1 decreased. However, DHQ rescued intracellular Nrf2 level and promoted nuclear translocation of Nrf2. DHQ scavenged TGF-β1-induced accumulation of reactive oxygen species, inhibited TGF-β1-induced Smad3 phosphorylation, and prevented TGF-β1-induced fibroblast activation and collagen synthesis in NRK-49F. Nrf2 knockdown could suppress the DHQ-mediated inhibitory effects on oxidative stress, Smad3 phosphorylation, fibroblast activation, and collagen deposition. Furthermore, DHQ ameliorated established renal fibrosis in UUO mice.

Conclusions: DHQ posed remarkable preventive and therapeutic effects on UUO-induced renal fibrosis and suppressed fibroblast activation by reducing oxidative stress and Smad3 phosphorylation via Nrf2 signaling. This study provided a mechanistic basis for the clinical application of DHQ in renal fibrosis treatment.

Keywords: Dihydroquercetin; Nuclear factor-erythroid-2-related factor 2; Oxidative stress; Renal tubulointerstitial fibrosis.

MeSH terms

  • Animals
  • Fibrosis
  • Hydrogen Peroxide / metabolism
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney / pathology
  • Kidney Diseases / drug therapy*
  • Kidney Diseases / metabolism
  • Kidney Diseases / pathology
  • Male
  • Mice, Inbred C57BL
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidative Stress / drug effects
  • Phosphorylation / drug effects
  • Protective Agents / pharmacology*
  • Quercetin / analogs & derivatives*
  • Quercetin / chemistry
  • Quercetin / pharmacology
  • Rats
  • Signal Transduction / drug effects*
  • Smad3 Protein / metabolism
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / pharmacology
  • Ureteral Obstruction / metabolism
  • Ureteral Obstruction / pathology

Substances

  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Protective Agents
  • Smad3 Protein
  • Smad3 protein, mouse
  • Transforming Growth Factor beta
  • Quercetin
  • taxifolin
  • Hydrogen Peroxide