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

doi:10.3390/toxins12060364

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.

Highlights

Aristolochic acids (AAs) are well-known nephrotoxins, while information regarding the attenuation of aristolochic acids (AAs)-induced toxicity is scarce
Under the circumstances of uremic inflammation, uremic cachexia highly cachexia highly prevalent among chronic kidney disease (CKD) patients is featured with anorexia, increased energy prevalent among CKD patients is featured with anorexia, increased energy expenditure and decreased expenditure and decreased body weight (BW) and protein stores [17]
The scatter diagram illustrated positive correlations between plasma correlations between plasma concentrations of BUN, p-cresyl sulfate (PCS), indoxyl sulfate (IS) and Cr were robust (Figure 1B), concentrations of BUN, PCS, IS and Cr were robust (Figure 1B), indicating that renal dysfunction led to indicating that renal dysfunction led to the accumulation of various uremic toxins in the circulation

Summary

Introduction

Aristolochic acids (AAs) are well-known nephrotoxins, while information regarding the attenuation of AAs-induced toxicity is scarce. AAs primarily damage renal tubulointerstitium, culminating in profound tubulointerstitial fibrosis (TIF), end-stage kidney disease (ESKD) and fatal urothelial cancer [1]. TIF is the outcome of multiple forms of chronic kidney disease (CKD), which is commonly caused by diabetes, hypertension and nephrotoxins [2]. The irreversible renal fibrosis and sustained retention of uremic toxins from the dietary-protein intake play a pivotal role in CKD pathogenesis [3]. In parallel with a decline in renal function, a myriad of uremic retention solutes exhibit pro-oxidant, pro-inflammation and pro-fibrotic effects on renal injury, leading to a vicious cycle [4,5]. An accumulation of uremic toxins following impaired renal clearance inhibits renal metabolic capacity and induces progressive TIF [6,7]

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