MSC-Derived Small Extracellular Vesicles Alleviate Renal Fibrosis in Hyperuricemic Nephropathy via Suppression of Epithelial Mesenchymal Transition.

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.