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

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.

Propolis in Metabolic Syndrome and Its Associated Chronic Diseases: A Narrative Review

“…Histological analysis showed that propolis-treated renal tissue after ischemic-reperfusion had a significantly lower tubular necrosis score [123]. Propolis also inhibited pro-inflammatory signaling pathways, namely, SMAD 2/3-dependent and SMAD-independent JNK/ERK activation in the signaling cascades of TGF-β family, that have been implicated in the development of tubulointerstitial fibrosis in advanced chronic kidney disease in animal models [124].…”

Reduced Expression of Metallothionein-I/II in Renal Proximal Tubules Is Associated with Advanced Chronic Kidney Disease

“…In addition, AA could be obtained from herbs, food, or some plant extracts [ 3 , 4 ]. The major characteristics of extensive tubulointerstitial fibrosis and the scar formation accompanied by renal tubular atrophy have been found in mouse and human AAN [ 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. Recent studies have revealed that AAI causes severe a reduction in the capillaries around the renal tubules, leading to hypoxia and the death of the renal tubular epithelial cells [ 5 , 6 , 7 , 8 , 9 , 10 , 11 ].…”

“…The major characteristics of extensive tubulointerstitial fibrosis and the scar formation accompanied by renal tubular atrophy have been found in mouse and human AAN [ 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. Recent studies have revealed that AAI causes severe a reduction in the capillaries around the renal tubules, leading to hypoxia and the death of the renal tubular epithelial cells [ 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. Furthermore, AAI increased the expression of fibrotic cytokine transforming growth factor 1 (TGF-1) and connective tissue growth factor (CTGF), which enhance fibrosis and scar formation [ 5 , 6 , 11 ].…”

“…Recent studies have revealed that AAI causes severe a reduction in the capillaries around the renal tubules, leading to hypoxia and the death of the renal tubular epithelial cells [ 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. Furthermore, AAI increased the expression of fibrotic cytokine transforming growth factor 1 (TGF-1) and connective tissue growth factor (CTGF), which enhance fibrosis and scar formation [ 5 , 6 , 11 ]. According to previous studies, the symptoms of AAN mice are very similar to those in patients with CKD [ 1 , 2 , 3 , 4 ].…”

Two New Aristolochic Acid Analogues from the Roots of Aristolochia contorta with Significant Cytotoxic Activity

“…Specific organic anion transporters mechanism of aristolochic acid derivatives into renal cells may greatly contribute to AA-mediated nephrotoxicity [ 12 ]. Other mechanisms, involving SMAD 2/3 and JNK/ERK pathways, mitochondrial/caspase apoptotic pathways, oxidative stress, microRNAs and mRNAs, might contribute to nephrotoxicity [ 13 , 14 , 15 ]. The progressive lesions and genotoxicity initiated by aristolochic acids are irreversible, and no effective therapeutic treatment for nephrotoxicity has been established up to now.…”