Pterostilbene alleviates fructose-induced renal fibrosis by suppressing TGF-β1/TGF-β type I receptor/Smads signaling in proximal tubular epithelial cells

Eur J Pharmacol. 2019 Jan 5;842:70-78. doi: 10.1016/j.ejphar.2018.10.008. Epub 2018 Oct 16.

Abstract

High dietary fructose is a key causative factor in the development of renal fibrosis. Pterostilbene has anti-fibrotic effect. Understanding the action mechanism of pterostilbene in fructose-induced renal fibrosis remains as a challenge. Here, fructose feeding was found to promote the progress of epithelial-to-mesenchymal transition (EMT) of proximal tubule epithelial cells (PTECs) and collagen deposition in renal cortex of rats with tubulointerstitial fibrosis. Simultaneously, it impaired insulin receptor (IR)/insulin receptor substrate-1 (IRS-1)/protein kinase B (Akt) pathway, and increased transforming growth factor-beta 1 (TGF-β1) and TGF-β type I receptor to enhance phosphorylation of drosophila mothers against decapentaplegic homolog 2 (Smad2) and Smad3, and Smad4 expression in rat kidney cortex. These changes were also observed in cultured PTECs HK-2 cells exposed to 5 mM fructose. The data from fructose-exposed HK-2 cells co-incubated with TGF-β type I receptor inhibitor further demonstrated that the activation of TGF-β1/TGF-β type I receptor/Smads signaling promoted renal tubular EMT and collagen accumulation. Pterostilbene was found to ameliorate fructose-induced renal fibrosis in rats. Importantly, pterostilbene improved IR/IRS-1/Akt pathway impairment and suppressed TGF-β1/TGF-β type I receptor/Smads signaling activation in vivo and in vitro, being consistent with its reduction of EMT and collagen deposition. Upregulation of IR/Akt signaling by pterostilbene was also confirmed in Akt inhibitor (MK-2206 2HCl) or IR inhibitor (GSK1904529A)-treated HK-2 cells. Taken together, pterostilbene may be a promising therapeutic agent for the treatment of fructose-induced kidney fibrosis with insulin signaling impairment.

Keywords: EMT; Fructose; PTECs; Pterostilbene; Renal fibrosis.

MeSH terms

  • Animals
  • Cell Line
  • Collagen / metabolism
  • Cytoprotection / drug effects
  • Epithelial Cells / drug effects
  • Epithelial Cells / pathology*
  • Epithelial-Mesenchymal Transition / drug effects
  • Fibrosis
  • Fructose / adverse effects*
  • Insulin / metabolism
  • Kidney Tubules, Proximal / drug effects
  • Kidney Tubules, Proximal / metabolism
  • Kidney Tubules, Proximal / pathology*
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Transforming Growth Factor-beta Type I / metabolism*
  • Signal Transduction / drug effects
  • Smad Proteins / metabolism*
  • Stilbenes / pharmacology*
  • Transforming Growth Factor beta1 / metabolism*

Substances

  • Insulin
  • Smad Proteins
  • Stilbenes
  • Transforming Growth Factor beta1
  • pterostilbene
  • Fructose
  • Collagen
  • Receptor, Transforming Growth Factor-beta Type I