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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

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Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, Taiwan
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Division of Nephrology, Department of Internal Medicine, En Chu Kong Hospital, New Taipei City 237, Taiwan
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Graduate Institute of Aerospace and Undersea Medicine, Academy of Medicine, National Defense Medical Center, Taipei 114, Taiwan
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Department of Nursing, Yuanpei University of Medical Technology, Hsinchu 300, Taiwan
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Renal Care Joint Foundation, New Taipei City 220, Taiwan
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Graduate Institution of Biomedical and Pharmaceutical Science, College of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
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School of Biomedical Engineering, Taipei Medical University, Taipei 110, Taiwan
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Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan
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Division of Nephrology, Department of Medicine, Fu Jen Catholic University Hospital, New Taipei City 242, Taiwan
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Department of Nephrology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan
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Department of Biotechnology and Animal Science, National Ilan University, Yilan 260, Taiwan
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Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
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Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan
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Department of Biotechnology and Pharmaceutical, Yuanpei University, Hsinchu 300, Taiwan
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School of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
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Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
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Authors to whom correspondence should be addressed.
Toxins 2020, 12(6), 364; https://doi.org/10.3390/toxins12060364
Received: 24 April 2020 / Revised: 23 May 2020 / Accepted: 28 May 2020 / Published: 2 June 2020
(This article belongs to the Section Uremic Toxins)
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. View Full-Text
Keywords: aristolochic acid; uremic toxins; propolis extract; tubulointerstitial fibrosis; transforming growth factor-β; chronic kidney disease aristolochic acid; uremic toxins; propolis extract; tubulointerstitial fibrosis; transforming growth factor-β; chronic kidney disease
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Chang, J.-F.; Hsieh, C.-Y.; Lu, K.-C.; Chen, Y.-W.; Liang, S.-S.; Lin, C.-C.; Hung, C.-F.; Liou, J.-C.; Wu, M.-S. 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. Toxins 2020, 12, 364.

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