Renoprotective Effects of Maslinic Acid on Experimental Renal Fibrosis in Unilateral Ureteral Obstruction Model via Targeting MyD88

Abstract

Maslinic acid (MA), also named crategolic acid, is a pentacyclic triterpene extracted from fruits and vegetables. Although various beneficial pharmacological effects of MA have been revealed, its effect on renal fibrosis remains unclear. This study was designed to clarify whether MA could attenuate renal fibrosis and determine the putative underlying molecular mechanisms. We demonstrated that MA-treated mice with unilateral ureteral obstruction (UUO) developed a histological injury of low severity and exhibited downregulated expression of fibrotic markers, including α-smooth muscle actin (α-SMA), vimentin, and fibronectin by 38, 44 and 40%, and upregulated expression of E-cadherin by 70% as compared with untreated UUO mice. Moreover, MA treatment restored the expression levels of α-SMA, connective tissue growth factor, and vimentin to 10, 7.8 and 38% of those induced by transforming growth factor (TGF)-β in NRK49F cells. MA decreased expression of Smad2/3 phosphorylation and Smad4 in UUO kidneys and TGF-β treated NRK49F cells (p < 0.05, respectively). Notably, MA specifically interferes with MyD88, an adaptor protein, thereby mitigating Smad4 nuclear expression (p < 0.01 compared to TGF-β treated group) and ameliorating renal fibrotic changes (p < 0.01 for each fibrotic markers compared to TGF-β induced cells). In addition, in the UUO model and lipopolysaccharide-induced NRK49F cells, MA treatment decreased the expression of IL-1β, TGF-α and MCP-1, ICAM-1, associated with the suppression of NF-κB signaling. These findings suggest that MA is a potential agent that can reduce renal interstitial fibrosis, to some extent, via targeting TGF-β/Smad and MyD88 signaling.

β-Elemene Attenuates Renal Fibrosis in the Unilateral Ureteral Obstruction Model by Inhibition of STAT3 and Smad3 Signaling via Suppressing MyD88 Expression

“…The association of the MyD88 signaling factor with fibrosis has been reported [ 49 , 50 ]. In our previous report, it was demonstrated that silencing of MyD88 inhibits TGF-β stimulated fibrosis in NRK49F cells and reduces the protein expression levels of α-SMA, CTGF, and vimentin [ 51 ]. Notably, Xiu Qiong Fu et al showed that TLR4 ligands activate STAT3 through MyD88 in melanoma cells and that knockdown of MyD88 reduced the level of STAT3 phosphorylation without affecting total STAT3 protein levels [ 52 ].…”

Maslinic Acid Attenuates Ischemia/Reperfusion-Induced Acute Kidney Injury by Suppressing Inflammation and Apoptosis Through Inhibiting NF-κB and MAPK Signaling Pathway

“…Also, Mokhtari et al found that MA did not produce any cytotoxic effect, even at the highest doses used ( Mokhtari et al, 2020 ). Also, in our previous study, we treated MA at 20 mg/kg for 7 days and observed no side effects on mice ( Sun et al, 2021 ).…”

“…After 72 h of reperfusion, all mice were sacrificed. Mice in the IRI + MA group were injected intraperitoneally with MA at a dose of 20 mg/kg (dissolved in 20 µl DMSO) pre-treatment to the surgery procedure based on our previous report ( Sun et al, 2021 ). MA was injected intraperitoneally in two protocols: In protocol 1 (n = 8 in each group), the prescribed dose of 20 mg/kg was injected 24 h before the ischemic surgery and the same dose was injected every day thereafter until the day before execution; in protocol 2 (n = 6 in each group), the same dose was injected once 1 h before the ischemic surgery.…”

Recent Advances Regarding the Molecular Mechanisms of Triterpenic Acids: A Review (Part II)

“…In an in vitro study conducted to assess the effect and underlying mechanism of MA’s activity in renal fibrosis, MA downregulated MyD88 and TGF-β/Smad pathways, leading to the decrease of extracellular matrix proteins expression and pro-inflammatory cytokines, thus inhibiting renal fibroblast proliferation [ 215 ].…”