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

Abstract

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 db/db 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 db/db mice. Treatment with SMUP-Cells ameliorated all of these changes. Notably, Gremlin isoform 2 (Grem2) exhibited the most significant difference in expression according to the transcriptome analysis. The elevated expression of Grem2 in db/db mice was significantly reduced following SMUP-Cell treatment. In vitro, treatment with high glucose and cholesterol induced Grem2 expression in renal tubular epithelial cells (RTECs), while Grem2 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 Grem2 expression in RTECs.