Promising therapeutic effect of thapsigargin nanoparticles on chronic kidney disease through the activation of Nrf2 and FoxO1

Fong Yu Cheng, Yu Hsuan Lee, Yung Ho Hsu, I. Jen Chiu, Yu Jhe Chiu, Yuh Feng Lin, Hui Wen Chiu

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Pathophysiological states cause misfolded protein accumulation in the endoplasmic reticulum (ER). Then, ER stress and the unfolded protein response (UPR) are activated. Targeting ER stress may enhance the adaptive UPR and then protect the cell against pathogenic environments. In the present study, we utilized nanotechnology to synthesize thapsigargin nanoparticles (TG NPs) which induced ER stress and the UPR pathway, to study the role of ER stress and autophagy in chronic kidney disease (CKD). We found that the mRNA levels of ER stress- and autophagy-related molecules were elevated in the renal tissue of CKD patients compared to those of healthy individuals. Furthermore, TG NPs induced the UPR pathway and autophagy in HK-2 human kidney tubular epithelial cells. TG NPs protected HK-2 cells against oxidative stress-induced cell death through the activation of Nrf2 and FoxO1. The siRNA-mediated inhibition of Nrf2 or FoxO1 resulted in enhanced oxidative stress-induced cytotoxicity in HK-2 cells. In a mouse model of adenine diet-induced CKD, TG NPs and KIM-1-TG NPs ameliorated renal injury through the stimulation of ER stress and its downstream pathways. Our findings suggest that the induction of ER stress using pharmacological agents may offer a promising therapeutic strategy for preventing or interfering with CKD progression.

Original languageEnglish
Pages (from-to)9875-9892
Number of pages18
JournalAging
Volume11
Issue number21
DOIs
Publication statusPublished - Jan 1 2019

Keywords

  • Autophagy
  • Chronic kidney disease
  • Endoplasmic reticulum stress
  • FoxO1
  • Nrf2

ASJC Scopus subject areas

  • Ageing
  • Cell Biology

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