Sodium–Glucose Cotransporter 2-Mediated Glucose Uptake Contributes to Glycogen Accumulation in Clear Cell Renal Cell Carcinoma: Implications for Clear Cell Morphology and Potential Therapeutic Relevance

Clear cell renal cell carcinoma (ccRCC) is characterized by loss of the functional von Hippel–Lindau (VHL) complex and distinctive clear cell morphology associated with intracellular glycogen and lipid accumulation. However, the mechanism underlying glycogen storage remains unclear. This study was conducted to investigate the relationship between SGLT2, a glucose transporter predominantly expressed in proximal tubular epithelial cells; the cell of origin of ccRCC; and clear cell morphology in ccRCC. Using the VHL-null ccRCC cell line KMRC-1, we investigated the effects of the SGLT2 inhibitor dapagliflozin, SGLT2 knockdown, and VHL overexpression on cellular morphology, intracellular glycogen accumulation, and glucose uptake. Immunohistochemical expression of SGLT2, glucose transporter 1, and VHL was evaluated in morphologically heterogeneous ccRCC specimens. Periodic acid–Schiff (PAS) and PAS with diastase staining, together with quantitative image analysis of PAS-stained cells, showed that dapagliflozin treatment, SGLT2 knockdown, and VHL restoration reduced cytoplasmic area and cytoplasmic PAS staining intensity in KMRC-1 cells. In the fluorescent glucose uptake assay, dapagliflozin significantly reduced the fluorescence signal (p < 0.05). In paired intratumoral analyses of six VHL-deficient ccRCC specimens, SGLT2 immunohistochemical scores were significantly higher in clear cell components than in eosinophilic components (p = 0.026), whereas GLUT1 scores did not differ significantly (p = 0.850). These findings suggest that SGLT2-mediated glucose uptake contributes to glycogen accumulation and the glycogen-rich clear cell morphology of VHL-deficient ccRCC. The potential therapeutic relevance of SGLT2 inhibition in ccRCC warrants further investigation.