Mesenchymal Stem Cells Mediated Suppression of GREM2 Inhibits Renal Epithelial-Mesenchymal Transition and Attenuates the Progression of Diabetic Kidney Disease

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide. Despite advancements in various treatments, the prevalence of DKD continues to rise, leading to a significant increase in the demand for dialysis and kidney transplantation. This study aimed to evaluate the effects of a Small cell＋Ultra Potent＋Scale UP cell (SMUP-Cell), a type of human umbilical cord blood-derived mesenchymal stem cell, on DKD in the db/db mouse model of type 2 diabetes mellitus. After administering SMUP-Cells via tail vein injection in db/db mice, the animals were monitored over a three-month period. The <i>db/db</i> mice exhibited an increased urine albumin-to-creatinine ratio (UACR). However, the administration of SMUP-Cells resulted in a reduction of the UACR. The expression levels of desmin, α-smooth muscle actin, and fibronectin-markers of epithelial-mesenchymal transition (EMT)-as well as kidney injury molecule 1, a sensitive marker of tubular injury, were significantly elevated in <i>db/db</i> mice. Treatment with SMUP-Cells ameliorated all of these changes. Notably, Gremlin isoform 2 (<i>Grem2</i>) exhibited the most significant difference in expression according to the transcriptome analysis. The elevated expression of <i>Grem2</i> in <i>db/db</i> mice was significantly reduced following SMUP-Cell treatment. In vitro, treatment with high glucose and cholesterol induced <i>Grem2</i> expression in renal tubular epithelial cells (RTECs), while <i>Grem2</i> knockdown effectively prevented fibrosis and senescence induced by high glucose and cholesterol in RTECs. These observations suggest that SMUP-Cells inhibit the progression of DKD by inhibiting EMT through the reduction of <i>Grem2</i> expression in RTECs.