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

Autor: Yao Pang Chung, Chia Hung Liu, Chang-Mu Chen, Chen Tien Wu, Kuo Tong Huang, Siao Syun Guan, Chih-Kang Chiang, Shing-Hwa Liu
Rok vydání: 2020
Předmět:
Male
Pharmaceutical Science
Tetrazoles
Apoptosis
Pharmacology
urologic and male genital diseases
Kidney
chemistry.chemical_compound
0302 clinical medicine
Fibrosis
Drug Discovery
Endoplasmic Reticulum Chaperone BiP
0303 health sciences
Nephritis
biology
Endoplasmic Reticulum Stress
female genital diseases and pregnancy complications
medicine.anatomical_structure
030220 oncology & carcinogenesis
Molecular Medicine
medicine.symptom
medicine.drug
Signal Transduction
Ureteral Obstruction
Inflammation
Withania somnifera
Protective Agents
03 medical and health sciences
medicine
Renal fibrosis
Animals
Renal Insufficiency
Chronic
Withanolides
030304 developmental biology
business.industry
Biphenyl Compounds
biology.organism_classification
medicine.disease
Mice
Inbred C57BL
Candesartan
Disease Models
Animal
Complementary and alternative medicine
chemistry
Withaferin A
Benzimidazoles
business
Kidney disease
Zdroj: Phytomedicine : international journal of phytotherapy and phytopharmacology. 79
ISSN: 1618-095X
Popis: 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.
Databáze: OpenAIRE
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