Dual role of miR-21-enriched MSC-derived exosomes in diabetic nephropathy: therapeutic potential versus p53-driven pathogenicity

Diabetic nephropathy (DN) is a prevalent and devastating complication of diabetes mellitus and is characterized by tubular atrophy, interstitial fibrosis, lipid metabolism dysregulation, and oxidative stress. Mesenchymal stem cell-derived exosomes (MSCs-Exo) have demonstrated promise in attenuating these DN-associated pathologies through multiple mechanisms. However, microRNAs (e.g., miR-21) encapsulated within MSCs-Exo may also have deleterious effects on DN through discrete molecular pathways, and the underlying mechanisms remain unclear. This study aimed to elucidate the role of the miR-21/p53 signaling axis in the MSC-Exo-mediated modulation of DN progression and to define the dual role of miR-21 in both therapeutic and pathogenic contexts. DN models were established in vitro using high-glucose–treated HK2 cells and in vivo using C57BL/KsJ db/db mice. The effects of MSCs-Exo, an miR-21 mimic, and the p53 activator C16 on cell proliferation, lipid metabolism, fibrosis, and oxidative stress were evaluated. The outcomes were quantified using transmission electron microscopy, qRT‒PCR, Western blotting, ROS fluorescence, hematoxylin and eosin (HE) staining, periodic acid–Schiff (PAS) staining, and Masson’s trichrome staining. MSCs-Exo significantly restored the proliferation of high-glucose–treated HK2 cells and concomitantly downregulated the expression of miR-21 and p53 and the dysregulation of lipid metabolism, oxidative stress, and fibrosis. In vivo, MSCs-Exo improved glycemic control, lipid profiles, and renal function in diabetic mice but also attenuated tubular atrophy and collagen deposition. However, miR-21–enriched MSCs-Exo markedly activated p53 signaling, exacerbating ferroptosis, lipid accumulation, and fibrosis. Further pharmacologic activation of p53 with C16 worsened these pathological changes, confirming the central role of p53 in miR-21-mediated pathogenic effects. The MSC-Exo/miR-21/p53 signaling axis plays a critical role in attenuating DN progression. Nonetheless, elevated miR-21 levels in MSCs-Exo activate the p53 pathway and drive ferroptosis, lipid accumulation, and fibrosis, thereby exerting pronounced pathogenic effects. Regulating miR-21 loading in MSCs-Exo may be a key strategy for optimizing their therapeutic efficacy in DN.