Mesenchymal Stem Cell and Secretome Treatments Inhibit The mTOR–NOX4 Pathway in Diabetic Kidney Disease

Diabetic kidney disease (DKD) is a major complication of diabetes characterized by progressive renal dysfunction driven by oxidative stress and inflammation involving mTOR and NADPH oxidase (NOX) pathways. Mesenchymal stem cells (MSCs) have gained attention for their regenerative and immunomodulatory properties in attenuating DKD, but the mechanisms behind their protective effects are still being explored. Moreover, concerns regarding tumorigenic risks hinder their direct clinical use. In this study, we compared MSCs and their conditioned media (MSCs-CM; secretome) in a type 1 diabetic rodent model, demonstrating that both treatments attenuated glomerular injury, preserved podocyte integrity, reduced NOX4 expression and activity, and tempered inflammation, by inhibiting mTORC1 and mTORC2 signaling. Importantly, MSCs-CM replicated the renoprotective effects of MSCs, indicating that soluble factors mediate these benefits. To our knowledge, this is the first study to directly compare MSCs and their conditioned media (MSCs-CM) in diabetic kidney disease, revealing that MSCs-CM delivers equivalent therapeutic efficacy while circumventing the safety concerns inherent to cell-based therapies. These findings identify the mTOR/NOX axis as a therapeutic target and support MSCs-CM as a promising, safer cell-free alternative for DKD treatment, potentially advancing regenerative strategies to mitigate diabetic renal injury.