A cell-free therapeutic strategy using MSC-derived exosomes and activated platelet lysate for acute kidney injury induced by rhabdomyolysis

Abstract Rhabdomyolysis-induced acute kidney injury (AKI) is primarily driven by myoglobin-mediated tubular toxicity, leading to pronounced oxidative stress, inflammation, and apoptosis. Given the limited availability of effective targeted therapies, this study aimed to evaluate the efficacy of a combined cell-free approach using exosomes derived from adipose mesenchymal stem cells (EXO) and activated platelet lysate (PL) in enhancing renal recovery in a glycerol-induced rat model of AKI. Forty male Wistar rats were divided into five groups: control, glycerol-induced AKI, EXO, PL, and EXO + PL. Platelet lysate was characterized for growth factor content. Renal dysfunction was assessed by measuring serum creatinine, urea, and creatine kinase levels. Renal expression of genes related to inflammation, injury, and fibrotic remodeling was analyzed. Renal tissue levels of phosphorylated Smad3 (p-Smad3) and total Smad3 were determined. Histopathological examination and immunohistochemical staining for myoglobin and caspase-3 were performed to assess structural damage and apoptosis. Glycerol-induced AKI caused significant renal dysfunction, reflected by elevated serum markers, increased expression of inflammatory and injury-related genes (CD68, NF-κB, KIM-1, and TGF-β1), and reduced antioxidant signaling (Nrf2). These changes were accompanied by tubular damage, myoglobin accumulation, and increased apoptosis. EXO or PL monotherapy partially attenuated these alterations, whereas the combined EXO + PL treatment produced more pronounced effects, including reduced serum injury markers, decreased inflammatory gene expression, restoration of Nrf2 gene expression, and attenuation of apoptosis. In addition, EXO + PL treatment was associated with reduced phosphorylated Smad3 activation. Combined EXO + PL therapy alleviated rhabdomyolysis-induced AKI more effectively than monotherapies, supporting its potential as a promising cell-free therapeutic strategy that warrants further mechanistic validation.