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
Yuanxia Zou, Jiraporn Kantapan, Honglian Wang, Jianchun Li, Hongwei Su, Jian S. Dai, Nathupakorn Dechsupa, Li Wang
Abstract
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. 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. 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. 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.