Centella asiatica Extract Attenuates Kidney Fibrosis Through Reducing Mesenchymal Transition and Inflammation in Ureteral Ligation Model in Mice

Abstract

Background: Kidney fibrosis is the common final pathway of chronic kidney disease (CKD), and is characterized by inflammation, mesenchymal transition with myofibroblast formation and epithelial to mesenchymal transition (EMT). Centella asiatia (CeA) is an herb that has a reno-protective effect. However, its mechanism of action in kidney fibrosis has not been elucidated.Aim: To elucidate the effect of CeA in amelioration of kidney fibrosis in a unilateral ureteral obstruction (UUO) model and focus on mesenchymal transition and inflammation.Methods: Unilateral ureteral obstruction was performed in male Swiss-background mice (age: 2–3 months, weight: 30–40 g, UUO group n = 6) to induce kidney fibrosis. Two doses of CeA extract with oral administration, 210 and 840 mg/kg body weight were added in UUO (U+C210 and U+C840 groups, each n = 6). The sham operation procedure was performed for the control group (SO, n = 6). The mice were euthanized at day-14 after operation. Tubular injury and interstitial fibrosis area fractions in kidney tissues of the mice were quantified based on periodic acid-Schiff (PAS) and Sirius Red (SR) staining. Immunostaining was performed for examination of fibroblast (PDGFR-β), myofibroblast (α-SMA), Monocyte Chemoattractant Protein-1 (MCP-1) and macrophage (CD68), meanwhile double immunofluorescence was performed with PDGFR-β and α-SMA. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to examine mRNA expression of TGF-β, Collagen-1, Snail, E-cadherin, vimentin, fibroblast-specific protein 1 (FSP-1), CD68, toll-like receptor 4 (TLR4), and MCP-1.Results: We observed a significantly higher interstitial fibrosis area fraction and tubular injury (p < 0.001) with fibroblast expansion and myofibroblast formation in the UUO group than in the SO group. These findings were associated with higher mRNA expression of TGF-β, Collagen-1, Snail, vimentin, FSP-1, CD68, TLR4, and MCP-1 and lower mRNA expression of E-cadherin. The U+C840 group had a significantly lower tubular injury score and interstitial fibrosis area fraction, which associated with downregulation of mRNA expression of TGF-β, Collagen-1, Snail, vimentin, FSP-1, CD68, TLR4, and MCP-1, with upregulation of mRNA expression of E-cadherin. Immunostaining observation revealed the U+C840 group demonstrated reduction of macrophage infiltration and myofibroblast expansion.Conclusion: CeA treatment with dose-dependently ameliorates mesenchymal transition and inflammation in kidney fibrosis in mice.

Ethanolic Leaf Extract of Centella asiatica L. Possesses Nephroprotection in an Animal Model of Nephrotoxicity

“…CA reduced vascular remodelling, glomeruli injury by increasing antifibrotic factor activity, and inflammatory biomarkers restored renal injury in nephrectomy animals. [21][22][23] Different protective mechanisms could be responsible for Centella asiatica's nephroprotective effects. Previous research suggested that triterpenoid present in CA increased the activity of antioxidant enzymes and nuclear factor erythroid-2-related factor 2.…”

Proteomic analysis exploring the mechanism of bladder fibrosis induced by ketamine using a rat model

“…As an important indicator to evaluate the occurrence of fibrosis (11,12), the expression of the collagen I protein was significantly increased in the experimental group (P=0.0181) (Figure 2). The results show that after 8 weeks of tail vein injection, obvious fibrosis had occurred in the rat bladders.…”

Acteoside alleviates UUO-induced inflammation and fibrosis by regulating the HMGN1/TLR4/TREM1 signaling pathway

“… Tammaro et al (2013) reported that the expression of triggering receptor expressed on myeloid cells-1 (TREM-1) positive cells may be closely related to inflammation and fibrosis in the kidney, and more interestingly, its role may be achieved by amplifying the inflammatory signal of TLR4. The TLR4 pathway is a classic inflammatory pathway, and its role in renal inflammation and fibrosis has been reported in many articles ( Wang et al, 2020 ; Sari et al, 2021 ; Zhang et al, 2015 ). Mobility nucleosome-binding protein 1 (High-mobility group nucleosome-binding protein 1, HMGN1) is a natural TLR4 activator ( Jiang et al, 2021 ).…”