Iron-Quercetin complex enhances mesenchymal stem cell-mediated HGF secretion and c-Met activation to ameliorate acute kidney injury through the prevention of tubular cell apoptosis

Abstract

Background

Acute kidney injury (AKI) is a life-threatening clinical syndrome with no effective treatment currently available. This study aims to investigate whether Iron-Quercetin complex (IronQ) pretreatment can enhance the therapeutic efficacy of Mesenchymal stem cells (MSCs) in AKI and explore the underlying mechanisms.

Methods

A cisplatin-induced AKI model was established in male C57BL/6 mice, followed by the intravenous administration of 1x10ˆ6 MSCs or IronQ-pretreated MSCs (MSC^IronQ). Renal function, histology, and tubular cell apoptosis were analyzed three days post-treatment. In vitro, apoptosis was induced in mouse tubular epithelial cells (mTECs) using cisplatin, followed by treatment with MSCs or MSC^IronQ conditioned medium (CM). Apoptosis was evaluated using TUNEL assay, RT-PCR, and western blotting. Furthermore, RNA sequencing (RNA-seq) was performed on MSC^IronQ to explore the underlying mechanisms.

Results

Compared to MSC-treated AKI mice, those treated with MSC^IronQ showed significantly improved renal function and histological outcomes, with reduced tubular cell apoptosis. A similar effect was observed in cisplatin-treated mTECs exposed to MSC^IronQ-CM. Mechanistically, RNA-seq and subsequent validation revealed that IronQ treatment markedly upregulated the expression and secretion of hepatocyte growth factor (HGF) in MSCs. Furthermore, RNA interference or antibody-mediated neutralization of HGF effectively abolished the anti-apoptotic effects of MSC^IronQ on mTECs. This mechanistic insight was reinforced by pharmacological inhibition of c-Met, the specific receptor of HGF, in both in vitro and in vivo models.

Conclusions

IronQ pretreatment enhances MSCs efficacy in AKI by promoting HGF expression and secretion, activating the HGF/c-Met pathway to suppress tubular cell apoptosis. These findings indicate that IronQ improves MSC-based therapies and offers insights into molecular mechanisms, supporting the development of better AKI treatments.