Abstract
BackgroundExtracellular vesicles produced by bone marrow mesenchymal stem cells (BMSC-EVs) can play important roles in the repair of injured tissues. Though numerous studies have reported the effect of EVs on renal fibrosis, the underlying mechanisms remain unclear. We hypothesized that BMSC-EVs containing milk fat globule–epidermal growth factor–factor 8 (MFG-E8) could attenuate renal fibrosis by inhibiting the RhoA/ROCK pathway.MethodsWe investigated whether BMSC-EVs have anti-fibrotic effects in a rat model of renal fibrosis, in which rats were subjected to unilateral ureteral obstruction (UUO), as well as in cultured HK2 cells. Extracellular vesicles from BMSCs were collected and co-cultured with HK2 cells during transforming growth factor-β1 (TGF-β1) treatment. HK2 cells co-cultured with TGF-β1 were also treated with the ROCK inhibitor, Y-27632.ResultsCompared with the Sham group, UUO rats displayed fibrotic abnormalities, accompanied by an increased expression of α-smooth muscle actin and Fibronectin and reduced expression of E-cadherin. These molecular and pathological changes suggested increased inflammation in damaged kidneys. Oxidative stress, as evidenced by an increased level of MDA and decreased levels of SOD1 and Catalase, was also observed in UUO kidneys. Additionally, activation of cleaved caspase-3 and PARP1 and increased apoptosis in the proximal tubules confirmed tubular cell apoptosis in the UUO group. All of these phenotypes exhibited by UUO rats were suppressed by treatment with BMSC-EVs. However, the protective effect of BMSC-EVs was completely abolished by the inhibition of MFG-E8. Consistent with the in vivo results, treatment with BMSC-EVs reduced inflammation, oxidative stress, apoptosis, and fibrosis in HK-2 cells stimulated with TGF-β1 in vitro. Interestingly, treatment with Y-27632 protected HK-2 cells against inflammation and fibrosis, although oxidative stress and apoptosis were unchanged.ConclusionsOur results show that BMSC-EVs containing MFG-E8 attenuate renal fibrosis in a rat model of renal fibrosis, partly through RhoA/ROCK pathway inhibition.
Highlights
Extracellular vesicles produced by bone marrow mesenchymal stem cells (BMSC-EVs) can play important roles in the repair of injured tissues
We found that treatment with BMSCEVs triggered a clear decrease in the expression of the mesenchymal markers α-SMA and Fibronectin, while the expression of the epithelial marker Ecadherin was increased compared with Human renal proximal tubular epithelial (HK-2) cells stimulated by transforming growth factor-β1 (TGF-β1) but not when treated with Bone marrow mesenchymal stem cells (BMSCs)-EVs (Fig. 5a, b)
We found that BMSC-EVs can reduce renal fibrosis by producing milk fat globule– epidermal growth factor–factor 8 (MFG-E8), which inhibits the RhoA/ROCK pathway
Summary
Extracellular vesicles produced by bone marrow mesenchymal stem cells (BMSC-EVs) can play important roles in the repair of injured tissues. Though numerous studies have reported the effect of EVs on renal fibrosis, the underlying mechanisms remain unclear. Patients with CKD experience progressive deterioration of renal function that can progress to end-stage renal failure. Though considerable effort has been dedicated to finding ways to ameliorate renal fibrosis in these patients, few specific therapeutic strategies are available that effectively delay or prevent the progression of renal tubulointerstitial fibrosis (TIF) to end-stage renal failure [3, 4]. Bone marrow mesenchymal stem cells (BMSCs), a multipotent progenitor cell type capable of repair, regeneration, and immunomodulation, are widely seen as a promising therapeutic option for renal disease [5]. BMSCs are generally recognized for their ability to self-renew and differentiate into multiple lineages
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