Therapeutic targeting of aristolochic acid induced uremic toxin retention, SMAD 2/3 and JNK/ERK pathways in tubulointerstitial fibrosis: Nephroprotective role of propolis in chronic kidney disease

Jia Feng Chang, Chih Yu Hsieh, Kuo Cheng Lu, Yue Wen Chen, Shih Shin Liang, Chih Cheng Lin, Chi Feng Hung, Jian Chiun Liou, Mai Szu Wu

Research output: Contribution to journalArticlepeer-review

Abstract

The nephrotoxicity of aristolochic acids (AAs), p-cresyl sulfate (PCS) and indoxyl sulfate (IS) were well-documented, culminating in tubulointerstitial fibrosis (TIF), advanced chronic kidney disease (CKD) and fatal urothelial cancer. Nonetheless, information regarding the attenuation of AAs-induced nephropathy (AAN) and uremic toxin retention is scarce. Propolis is a versatile natural product, exerting anti-oxidant, anti-cancer and anti-fibrotic properties. We aimed to evaluate nephroprotective effects of propolis extract (PE) in a murine model. AAN was developed to retain circulating PCS and IS using C57BL/6 mice, mimicking human CKD. The kidney sizes/masses, renal function indicators, plasma concentrations of PCS/IS, tissue expressions of TIF, α-SMA, collagen IaI, collagen IV and signaling pathways in transforming growth factor-β (TGF-β) family were analyzed among the control, PE, AAN, and AAN-PE groups. PE ameliorated AAN-induced renal atrophy, renal function deterioration, TIF, plasma retention of PCS and IS. PE also suppressed α-SMA expression and deposition of collagen IaI and IV in the fibrotic epithelial-mesenchymal transition. Notably, PE treatment in AAN model inhibited not only SMAD 2/3-dependent pathways but also SMAD-independent JNK/ERK activation in the signaling cascades of TGF-β family. Through disrupting fibrotic epithelial-mesenchymal transition and TGF-β signaling transduction pathways, PE improves TIF and thereby facilitates renal excretion of PCS and IS in AAN. In light of multi-faced toxicity of AAs, PE may be capable of developing a new potential drug to treat CKD patients exposed to AAs.

Original languageEnglish
Article number364
JournalToxins
Volume12
Issue number6
DOIs
Publication statusPublished - Jun 2 2020

Keywords

  • Aristolochic acid
  • Chronic kidney disease
  • Propolis extract
  • Transforming growth factor-β
  • Tubulointerstitial fibrosis
  • Uremic toxins

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

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