Therapeutic effects of Nrf2-enhanced bone marrow mesenchymal stem cells on diabetic bladder dysfunction in mice

Diabetic bladder dysfunction (DBD) remains a prevalent and debilitating complication of diabetes, lacking effective therapeutic options. While bone marrow‑derived mesenchymal stem cells (BM‑MSCs) possess regenerative potential, their low post‑transplant survival and limited engraftment restrict clinical utility. This study investigates whether overexpression of nuclear factor erythroid 2‑related factor 2 (Nrf2), a master regulator of antioxidant responses, can enhance BM‑MSCs function and therapeutic efficacy in DBD. Nrf2‑overexpressing BM‑MSCs (Nrf2‑BM‑MSCs) were generated via lentiviral transduction. In vitro, Nrf2‑BM‑MSCs exhibited enhanced proliferation and paracrine activity, notably elevating IGF‑1 secretion via AKT/GSK‑3β pathway activation. Conditioned medium from Nrf2‑BM‑MSCs more effectively reduced apoptosis and ROS levels while promoting proliferation in high glucose‑treated primary bladder smooth muscle cells. In a murine DBD model, intravesical transplantation of Nrf2‑BM‑MSCs markedly improved urodynamic parameters, attenuated bladder fibrosis and apoptosis, and enhanced smooth muscle cell proliferation and microvascular regeneration compared to unmodified BM‑MSCs. Our findings demonstrate that Nrf2 gene modification amplifies BM‑MSCs survival, paracrine function, and antioxidant capacity via AKT/GSK‑3β signaling, substantially boosting their therapeutic potential in DBD. Engineered Nrf2‑BM‑MSCs thus represent a novel and promising cell‑based strategy for diabetic bladder dysfunction.