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.
Highlights
Chronic kidney disease (CKD) is a global public health problem, and its incidence is increasing concomitantly with the aging population, even in Indonesia
The interstitial fibrosis decreased to greater extent in the U+C840 group compared with the U+C210 and ureteral obstruction (UUO) groups (Figure 1)
The UUO group had significantly higher mRNA expression of Transforming growth factor- β (TGF-β) and Collagen-1 when compared to the SO group (p < 0.05) and a significantly higher protein level of α-smooth muscle antibody (α-SMA) (p 0.000) when compared to the SO group
Summary
Chronic kidney disease (CKD) is a global public health problem, and its incidence is increasing concomitantly with the aging population, even in Indonesia. The World Health Organization estimated approximately 58 million deaths due to kidney diseases and around 35 million deaths were attributed to CKD (Neuhofer and Pittrow, 2006; Levey et al, 2007). A survey conducted by the US Centers for Disease Control and Prevention reported an increase in the prevalence of CKD from 12% in 1988–1994 to 15% in 2003–2006, especially in people aged 60 years or above. Hypertension, or both, have a higher risk of developing CKD than those without these conditions. In the last decade in Indonesia, diabetic nephropathy was considered the main cause of CKD, in recent years, the cause has gradually shifted to hypertension (PERNEFRI, 2015). Its mechanism of action in kidney fibrosis has not been elucidated
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