Withaferin A protects against endoplasmic reticulum stress-associated apoptosis, inflammation, and fibrosis in the kidney of a mouse model of unilateral ureteral obstruction

Chang Mu Chen, Yao Pang Chung, Chia Hung Liu, Kuo Tong Huang, Siao Syun Guan, Chih Kang Chiang, Chen Tien Wu, Shing Hwa Liu

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Background: Withaferin A is a functional ingredient of a traditional medicinal plant, Withania somnifera, which has been broadly used in India for protecting against chronic diseases. This bioactive steroidal lactone possesses multiple functions such as anti-oxidation, anti-inflammation, and immunomodulation. Chronic kidney disease (CKD) is one of the major health problems worldwide with the high complication, morbidity, and mortality rates. The detailed effects and underlying mechanisms of withaferin A on CKD progression still remain to be clarified. Purpose: We aimed to investigate whether withaferin A treatment ameliorates the development of renal fibrosis and its related mechanisms in a CKD mouse model. Methods: A mouse model of unilateral ureteral obstruction (UUO) was used to mimic the progression of CKD. Male adult C57BL/6J mice were orally administered with 3 mg/kg/day withaferin A for 14 consecutive days after UUO surgery. Candesartan (5 mg/kg/day) was used as a positive control. Results: Both Withaferin A and candesartan treatments significantly ameliorated the histopathological changes and collagen deposition in the UUO kidneys. Withaferin A could significantly reverse the increases in the protein levels of pro-fibrotic factors (fibronectin, transforming growth factor-β, and α-smooth muscle actin), inflammatory signaling molecules (phosphorylated nuclear factor-κB-p65, interleukin-1β, and cyclooxygenase-2), and cleaved caspase-3, apoptosis, and infiltration of neutrophils in the UUO kidneys. The protein levels of endoplasmic reticulum (ER) stress-associated molecules (GRP78, GRP94, ATF4, CHOP, phosphorylated eIF2α, and cleaved caspase 12) were increased in the kidneys of UUO mice, which could be significantly reversed by withaferin A treatment. Conclusion: Withaferin A protects against the CKD progression that is, at least in part, associated with the moderation of ER stress-related apoptosis, inflammation, and fibrosis in the kidneys of CKD. Withaferin A may serve as a potential therapeutic agent for the development of CKD.

Original languageEnglish
Article number153352
JournalPhytomedicine
Volume79
DOIs
Publication statusPublished - Dec 2020

Keywords

  • Apoptosis
  • Chronic kidney disease
  • ER stress
  • Inflammation
  • Withaferin A

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine

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