Ganoderic acid hinders renal fibrosis via suppressing the TGF-β/Smad and MAPK signaling pathways

Abstract

Renal fibrosis is considered as the pathway of almost all kinds of chronic kidney diseases (CKD) to the end stage of renal diseases (ESRD). Ganoderic acid (GA) is a group of lanostane triterpenes isolated from Ganoderma lucidum , which has shown a variety of pharmacological activities. In this study we investigated whether GA exerted antirenal fibrosis effect in a unilateral ureteral obstruction (UUO) mouse model. After UUO surgery, the mice were treated with GA (3.125, 12.5, and 50 mg· kg −1 ·d − 1 , ip) for 7 or 14 days. Then the mice were sacrificed for collecting blood and kidneys. We showed that GA treatment dose-dependently attenuated UUO-induced tubular injury and renal fibrosis; GA (50 mg· kg −1 ·d − 1 ) significantly ameliorated renal disfunction during fibrosis progression. We further revealed that GA treatment inhibited the extracellular matrix (ECM) deposition in the kidney by suppressing the expression of fibronectin, mainly through hindering the over activation of TGF-β/Smad signaling. On the other hand, GA treatment significantly decreased the expression of mesenchymal cell markers alpha-smooth muscle actin (α-SMA) and vimentin, and upregulated E-cadherin expression in the kidney, suggesting the suppression of tubular epithelial-mesenchymal transition (EMT) partially via inhibiting both TGF-β/Smad and MAPK (ERK, JNK, p38) signaling pathways. The inhibitory effects of GA on TGF-β/Smad and MAPK signaling pathways were confirmed in TGF-β1-stimulated HK-2 cell model. GA-A, a GA monomer, was identified as a potent inhibitor on renal fibrosis in vitro. These data demonstrate that GA or GA-A might be developed as a potential therapeutic agent in the treatment of renal fibrosis.

<p>Emodin Retarded Renal Fibrosis Through Regulating HGF and TGFβ–Smad Signaling Pathway</p>

“…αSMA plays key roles in epithelial-mesenchymal transition (EMT). [34][35][36] In this study, the findings indicated that HGF can inactivate αSMA. Emodin significantly enhanced the suppressive effect of HGF on this protein.…”

Targeting UDP‐glucose dehydrogenase inhibits ovarian cancer growth and metastasis

“…Our immunoblot analysis revealed decreased expression levels of MMP‐2 and MMP‐9 in UGDH‐silenced ovarian cancer cells, which is consistent with previous reports. There is growing evidence that the ERK/MAPK pathway participates in the regulation of EMT‐related factors such as E‐cadherin, vimentin, SNAIL, SIP‐1 and TWIST 47‐49 . Our data demonstrated that UGDH overexpressing TOV21G HI cells express higher levels of phosphorylated‐ERK, MMP‐2, SIP‐1 and SNAIL, whereas knockdown of UGDH leads to decreases in these markers, indicating that UGDH is involved in regulating ERK, MMP‐2 and EMT markers in ovarian cancer.…”

“…There is growing evidence that the ERK/ MAPK pathway participates in the regulation of EMT-related factors such as E-cadherin, vimentin, SNAIL, SIP-1 and TWIST. [47][48][49] Our data demonstrated that UGDH overexpressing TOV21G HI cells express higher levels of phosphorylated-ERK, MMP-2, SIP-1 and SNAIL, whereas knockdown of UGDH leads to decreases in these markers, indicating that UGDH is involved in regulating ERK, MMP-2 and EMT markers in ovarian cancer. We also revealed that knockdown of UGDH inhibits EMT, possibly through the ERK/MAPK pathway (Figure 7).…”

Transient Receptor Potential Channel 6 Knockout Ameliorates Kidney Fibrosis by Inhibition of Epithelial–Mesenchymal Transition

“…Studies have found that EMT is of profound significance in fibrosis and pervasive in different organs, such as the lungs, lens, liver, and kidney (Liang et al, 2014 ; Kong et al, 2015 ; Yang et al, 2019 ; Yao et al, 2019 ). Furthermore, EMT has been observed to improve the onset of kidney fibrosis, and fibrotic damages could be alleviated by repressing the process of EMT (Du et al, 2012 ; Geng et al, 2019 ). Clinical studies have suggested that EMT, as the early onset element of interstitial fibrosis in the kidney, is confirmed in diabetic patients (Hills and Squires, 2011 ; Carew et al, 2012 ).…”