Polysaccharides extracted from balanophora polyandra Griff (BPP) ameliorate renal Fibrosis and EMT via inhibiting the Hedgehog pathway

Abstract

Renal interstitial fibrosis (RIF) is a crucial pathological change leading to chronic kidney disease (CKD). Currently, no effective medicines have been available for treating it. In our research, we examined the effects of polysaccharides extracted from Balanophora polyandra Griff (BPPs) on kidney fibrosis and epithelial to mesenchymal transition (EMT) in vivo and in vitro, aiming to explore the underlying mechanisms. By using the mice with unilateral urethral obstruction (UUO) as experimental subjects, we examined the medicinal values of BPPs on alleviating RIF. The effects of BPPs were evaluated by examining the histological staining and relative mRNA and protein expression levels of the related genes. The possible underlying mechanisms were further explored with human normal renal proximal tubular epithelia (HK‐2 cells) as in vitro model. In UUO mice, BPP treatment could significantly alleviate interstitial fibrosis through reducing the components (Collagens I, III and IV) of extracellular matrix (ECM), and reducing the activation of fibroblasts producing these components, as revealed by inhibiting the hallmarks (fibronectin and α‐SMA) of fibroblast activation. Furthermore, BPP administration increased the expression levels of matrix metalloproteinases (MMPs) and declined those of tissue inhibitors of metalloproteinases (TIMPs). BPPs markedly ameliorated EMT in both the kidneys of UUO mice and TGF‐β1 treated HK‐2 cells. Moreover, BPP treatment decreased the expression levels of several transcriptional factors involved in regulating E‐cadherin expression, including snail, twist and ZEB1. Additionally, the Hedgehog pathway was found to be closely correlated with renal fibrosis and EMT. Altogether, our results clearly demonstrated that BPP treatment effectively inhibited the Hedgehog pathway both in renal tissues of UUO mice and TGF‐β1‐treated HK‐2 cells. Thus, BPPs ameliorated RIF and EMT in vivo and in vitro via suppressing Hedgehog signalling pathway.

Carvacrol preserves antioxidant status and attenuates kidney fibrosis via modulation of TGF-β1/Smad signaling and inflammation

“…35 TGF-β is the most prominent inducer of EMT, and several researchers reported the stimulation of the EMT program and the appearance of myofibroblast markers in the UUO-induced kidneys. 34,36 In line with these studies, our results revealed low renal E-cadherin levels and a substantial increase in the expression of vimentin and α-SMA in the kidneys of the UUO group, implying the dysregulated cellular adhesion of tubular epithelial and myofibroblast activation. Moreover, our in vitro data also confirmed the activation of the EMT program in renal tubular epithelial NRK 52E cells upon TGF-β induction.…”

“…Simultaneously, the tubular epithelial cells deficient in adhesion markers attain myofibroblast features distinguished by the production of α-SMA, vimentin, and fibronectin. 34 In particular, myofibroblasts are considered the primary source of ECM in interstitial space and are involved in aggravating the fibrogenic transformation of the kidneys. 35 TGF-β is the most prominent inducer of EMT, and several researchers reported the stimulation of the EMT program and the appearance of myofibroblast markers in the UUO-induced kidneys.…”

Research Progress of Chinese Herbal Medicine Intervention in Renal Interstitial Fibrosis

“…Renal tubular epithelial phenotypic transformation (EMT) is characterized by the transformation of the epithelial phenotype into a fibroblast-like mesenchymal phenotype, in which E-cadherin expression is reduced, and N-cadherin expression is increased. Epithelial cells lose top base polarity and, on the other hand, intercellular adhesion and gain mesenchymal properties ( Liu et al, 2020 ; Li L. et al, 2021 ). This change is critical, not just in renal fibrosis, but in various biological processes such as cancer progression, organization palingenesis, embryo growth, and wound coalescence.…”

“…Studies have shown that BPP administration inhibited the hedgehog signaling pathway. Therefore, BPPs can suppress the EMT process by attenuating the activity of the hedgehog signal conduction, thereby improving RIF ( Briscoe, 2009 ; Jenkins, 2009 ; Ding et al, 2012 ; Rauhauser et al, 2015 ; Li L. et al, 2021 ). Sedum is extracted from rhodiola rosea and widely used in the clinic.…”

NLRP3-mediated pyroptosis in diabetic nephropathy

“…The activation of hedgehog signaling has been shown to be associated with EMT in liver cancer cells ( Ding et al, 2017 ). In the UUO model, inhibition of hedgehog signaling pathway was also demonstrated to improve EMT in HK-2 cells ( Li et al, 2021c ). In the DN model, Zhao et al found that hyperglycemia stimulated the expression of the Hhip by enhancing the generation of ROS, and TGF-β1/Smad2 pathway was also activated, which promoted the transition of glomerular endothelial cells to the mesenchyme.…”