Abstract
With limited therapeutic intervention in preventing the progression to end-stage renal disease, chronic kidney disease (CKD) remains a global health-care burden. Aristolochic acid (AA) induced nephropathy is a model of CKD characterised by inflammation, tubular injury, and interstitial fibrosis. Human liver stem cell-derived extracellular vesicles (HLSC-EVs) have been reported to exhibit therapeutic properties in various disease models including acute kidney injury. In the present study, we aimed to investigate the effects of HLSC-EVs on tubular regeneration and interstitial fibrosis in an AA-induced mouse model of CKD. NSG mice were injected with HLSC-EVs 3 days after administering AA on a weekly basis for 4 weeks. Mice injected with AA significantly lost weight over the 4-week period. Deterioration in kidney function was also observed. Histology was performed to evaluate tubular necrosis, interstitial fibrosis, as well as infiltration of inflammatory cells/fibroblasts. Kidneys were also subjected to gene array analyses to evaluate regulation of microRNAs (miRNAs) and pro-fibrotic genes. The effect of HLSC-EVs was also tested in vitro to assess pro-fibrotic gene regulation in fibroblasts cocultured with AA pretreated tubular epithelial cells. Histological analyses showed that treatment with HLSC-EVs significantly reduced tubular necrosis, interstitial fibrosis, infiltration of CD45 cells and fibroblasts, which were all elevated during AA induced injury. At a molecular level, HLSC-EVs significantly inhibited the upregulation of the pro-fibrotic genes α-Sma, Tgfb1, and Col1a1 in vivo and in vitro. Fibrosis gene array analyses revealed an upregulation of 35 pro-fibrotic genes in AA injured mice. Treatment with HLSC-EVs downregulated 14 pro-fibrotic genes in total, out of which, 5 were upregulated in mice injured with AA. Analyses of the total mouse miRnome identified several miRNAs involved in the regulation of fibrotic pathways, which were found to be modulated post-treatment with HLSC-EVs. These results indicate that HLSC-EVs play a regenerative role in CKD possibly through the regulation of genes and miRNAs that are activated during the progression of the disease.
Highlights
Chronic kidney disease (CKD) is a pathology that affects billions of individuals globally [1]
Body weight of aristolochic acid (AA) mice injected with human liver stem cell (HLSC)-extracellular vesicles (EVs) increased gradually reaching a significant difference at week 4 compared to mice treated with AA alone
Mice treated with HLSC-EVs had significantly reduced levels of serum creatinine compared to mice treated with AA alone or with Fibro-EV, which served as a negative control (Figure 1C)
Summary
Chronic kidney disease (CKD) is a pathology that affects billions of individuals globally [1]. Treatment for end-stage CKD is limited to haemodialysis and kidney transplantation, both of which are restricted to financial restraint and/or availability of donor kidneys [2]. Interstitial fibrosis, a hallmark of CKD is accepted as an independent contributor/predictor of disease progression, making it a potential target for therapy [3]. Aristolochic acid nephropathy (AAN) is a rapidly progressing form of kidney disease that occurs in patients who have ingested plants containing aristolochic acid (AA) as part of traditional herbal therapy (Chinese herb nephropathy) or as a food contaminant (Balkan endemic nephropathy) [5]. AAN is predominantly characterised by interstitial fibrosis accompanied with tubular atrophy and EMT that eventually progresses towards end-stage renal disease [5]. Various pathways have been implicated in kidney fibrosis, the transforming growth factor beta (TGFβ) signalling pathway remains to be a major contributor [4]
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