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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

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

  • Yujiro Nagata1,2
  • Ikko Tomisaki1
  • Takuo Matsukawa1
  • Nguyen Thu Quynh1
  • Yuto Tsubonuma1
  • Yoshihiro Sugita1
  • Aya Nawata3
  • Keiji Kokubu4
  • Ryoko Baba4
  • Hiroyuki Morimoto4
  • Kohei Ogawa2
  • Koichiro Wada2
1 more authors
  • Naohiro Fujimoto1,5
5 affiliations
  1. 1Department of Urology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu 807-8555, Fukuoka, Japan
  2. 2Department of Urology, Shimane University Faculty of Medicine, Izumo 693-8501, Shimane, Japan
  3. 3Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu 807-8555, Fukuoka, Japan
  4. 4Department of Anatomy, School of Medicine, University of Occupational and Environmental Health, Kitakyushu 807-8555, Fukuoka, Japan
  5. 5Department of Urology, Kurate Hospital, Kurate 807-1311, Fukuoka, Japan
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{nagata2026sodiumglucose,
  title = {{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}},
  author = {Yujiro Nagata and Ikko Tomisaki and Takuo Matsukawa and Nguyen Thu Quynh and Yuto Tsubonuma and Yoshihiro Sugita and Aya Nawata and Keiji Kokubu and Ryoko Baba and Hiroyuki Morimoto and Kohei Ogawa and Koichiro Wada and Naohiro Fujimoto},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = oct,
  doi = {10.3390/ijms27209128},
  url = {https://www.mdpi.com/1422-0067/27/20/9128},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - 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
AU  - Yujiro Nagata
AU  - Ikko Tomisaki
AU  - Takuo Matsukawa
AU  - Nguyen Thu Quynh
AU  - Yuto Tsubonuma
AU  - Yoshihiro Sugita
AU  - Aya Nawata
AU  - Keiji Kokubu
AU  - Ryoko Baba
AU  - Hiroyuki Morimoto
AU  - Kohei Ogawa
AU  - Koichiro Wada
AU  - Naohiro Fujimoto
PY  - 2026
DA  - 2026/10/01
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27209128
UR  - https://www.mdpi.com/1422-0067/27/20/9128
AB  - 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.
SN  - 1422-0067
ER  -