Mechanism of ultrasound-guided renal parenchymal injection of MSCs for the treatment of chronic kidney disease: down-regulated SGK1 promotes M2 macrophage polarization.

Abstract

BACKGROUND: Chronic kidney disease (CKD) often progresses to renal fibrosis, leading to irreversible kidney damage and a decline in renal function. This study explores the therapeutic effects of ultrasound-guided mesenchymal stem cells (MSCs) infusion in CKD, focusing on the regulatory mechanism in macrophage polarization and fibrosis regulation. METHODS: CKD models were established in Sprague-Dawley rats via intravenous injection of doxorubicin, and MSCs infusion treatment was performed on the renal parenchyma of the model rats under ultrasound guidance. Meanwhile, transforming growth factor beta 1 (TGF-β1)-stimulated HK-2 cells or THP1-derived macrophage were co-cultured with MSCs to establish an in vitro cellular model. RNA sequencing was employed to identify differentially expressed genes. Furthermore, western blotting, immunofluorescence, and ELISA, were carried out to assess fibrosis, inflammation, and macrophage polarization. RESULTS: Ultrasound-guided MSCs infusion into the renal parenchyma effectively alleviated the pathological damage and fibrosis, and promoted M2 macrophage polarization in the renal tissues of CKD model rats. In vitro, co-culture with MSCs also significantly promoted M2 polarization of macrophages, reduced the levels of pro-inflammatory cytokines, and decreased TGF-β1-induced fibrosis in HK-2 cells. Notably, MSCs treatment significantly downregulated serum and glucocorticoid-regulated kinase 1 (SGK1) expression in CKD model rats or cells, while overexpression of SGK1 reversed MSCs-induced M2 macrophage polarization. Mechanistically, MSCs downregulated SGK1 expression to inactivate the downstream nuclear factor kappa-B pathway, which plays a role in inflammation and fibrosis. CONCLUSION: Ultrasound-guided MSCs injection into the renal parenchyma provides an efficient and precise therapeutic approach for CKD. MSCs promote macrophage M2 polarization and exert anti-fibrotic effects in CKD by downregulating SGK1 expression.