Tissue engineering and regenerative medicine · 2026
MSC-Derived Small Extracellular Vesicles Alleviate Renal Fibrosis in Hyperuricemic Nephropathy via Suppression of Epithelial Mesenchymal Transition.
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You Benshuai, Hu Haitao, Wei Jing, Xu Yun, Zhou Chenglin
Аннотация
BACKGROUND: Hyperuricemic nephropathy (HN) arises from excessive accumulation of uric acid, leading to subsequent renal injury. Mesenchymal stem cells-derived small extracellular vesicles (MSC-sEVs) have demonstrated beneficial effects in promoting tissue repair across various injury models. However, their potential therapeutic role in HN remains unknown.
METHODS: We isolated and characterized MSC-sEVs by transmission electron microscopy, nanoparticle tracking analysis, and Western blotting. A rat model of HN was established by daily administration of adenine and potassium oxonate for three weeks, after which MSC-sEVs were intravenously injected. Renal function, histopathological changes, and fibrotic markers were assessed, while the involvement of epithelial-mesenchymal transition (EMT) was examined both in vivo and in UA-treated HK-2 cells. Regenerative and anti-fibrotic outcomes were examined through Masson's trichrome staining and immunohistochemistry (α-SMA).
RESULTS: Rats with HN exhibited significant renal dysfunction and marked interstitial fibrosis. MSC-sEVs treatment significantly improved renal function, as evidenced by reduced serum creatinine and blood urea nitrogen, and attenuated tubulointerstitial fibrosis, collagen deposition, and α-SMA expression in HN rats. Mechanistically, UA induced a classic EMT phenotype in renal tubular cells in vivo and in vitro, characterized by downregulation of E-cadherin and upregulation of N-cadherin and vimentin, all of which were markedly reversed by MSC-sEVs. Notably, miRNA sequencing revealed that MSC-sEVs are enriched in multiple miRNAs that have been previously reported to target EMT-associated signaling pathways, suggesting a potential miRNA-mediated mechanism.
CONCLUSION: Our study found that MSC-sEVs can effectively reverse renal EMT in HN, thereby promoting the restoration of renal function, revealing a possible mechanism by which MSC-sEVs treatment in renal fibrosis associated with HN. Taken together, this study provides a foundation for innovative therapeutic approaches and advanced pharmacological strategies for HN.
METHODS: We isolated and characterized MSC-sEVs by transmission electron microscopy, nanoparticle tracking analysis, and Western blotting. A rat model of HN was established by daily administration of adenine and potassium oxonate for three weeks, after which MSC-sEVs were intravenously injected. Renal function, histopathological changes, and fibrotic markers were assessed, while the involvement of epithelial-mesenchymal transition (EMT) was examined both in vivo and in UA-treated HK-2 cells. Regenerative and anti-fibrotic outcomes were examined through Masson's trichrome staining and immunohistochemistry (α-SMA).
RESULTS: Rats with HN exhibited significant renal dysfunction and marked interstitial fibrosis. MSC-sEVs treatment significantly improved renal function, as evidenced by reduced serum creatinine and blood urea nitrogen, and attenuated tubulointerstitial fibrosis, collagen deposition, and α-SMA expression in HN rats. Mechanistically, UA induced a classic EMT phenotype in renal tubular cells in vivo and in vitro, characterized by downregulation of E-cadherin and upregulation of N-cadherin and vimentin, all of which were markedly reversed by MSC-sEVs. Notably, miRNA sequencing revealed that MSC-sEVs are enriched in multiple miRNAs that have been previously reported to target EMT-associated signaling pathways, suggesting a potential miRNA-mediated mechanism.
CONCLUSION: Our study found that MSC-sEVs can effectively reverse renal EMT in HN, thereby promoting the restoration of renal function, revealing a possible mechanism by which MSC-sEVs treatment in renal fibrosis associated with HN. Taken together, this study provides a foundation for innovative therapeutic approaches and advanced pharmacological strategies for HN.