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 mammalian target of rapamycin (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 DKD, 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.

Despite advances in diabetes management, diabetic kidney disease (DKD) remains a leading cause of end-stage renal disease. We investigated whether mesenchymal stem cells (MSCs) and their conditioned medium, containing the MSC-derived secretome, protect against DKD by modulating the mammalian target of rapamycin (mTOR)/NADPH oxidase (NOX) pathway. MSCs and MSCs-conditioned medium both reduced kidney injury, podocyte structural integrity, oxidative stress, and inflammation by inhibiting mTORC1/mTORC2 and NOX4. MSCs-conditioned medium offers a safe, secretome-based, cell-free approach for DKD therapy.