Mesenchymal Stem Cells Attenuate Podocyte Injury in Diabetic Nephropathy Through the Promotion of Type 2 Macrophage Polarization

Abstract

Diabetic nephropathy (DN), recognized as the leading cause of end-stage renal disease globally, necessitates novel therapeutic development. While mesenchymal stromal cells (MSCs) demonstrate therapeutic potential in DN management, their precise mechanisms require systematic elucidation. This study investigated the link between DN and inflammation activation, as well as the pathophysiological significance of MSC-mediated macrophage polarization and podocyte injury repair during this progression. We administered MSCs to streptozotocin-induced diabetic rats via tail vein injection and co-cultured podocytes and MSCs under high-glucose (HG) conditions. Subsequently, we assessed M2-like macrophage polarization and inflammation levels both in vitro and in vivo. In addition, we observed the distribution and homing of MSCs in vivo through ⁸⁹Zr labeling. Our results revealed that HG increased podocyte apoptosis and inflammation in both podocyte and diabetic rats. Treatment with MSCs attenuated inflammation, promoted M2-like macrophage polarization in podocyte under HG conditions as well as in diabetic rats, ultimately ameliorating kidney injury. Importantly, it was observed that MSCs homed to the kidney of DN rats, thereby exerting their therapeutic effects. Collectively, our findings demonstrate that MSCs exhibit renal homing capacity in diabetic kidney and protect podocytes from inflammation by promoting M2 macrophage polarization, thereby establishing MSCs as a promising therapeutic cell-free strategy for DN.