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Abstract: FR-PO731

Protective Role of Active Vitamin D in Transforming Growth Factor (TGF)-β1-Associated Podocyte Injury through Inhibition of p21 Upregulation

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

  • Wada, Takehiko, Toranomon Hospital, Tokyo, Japan
  • Sawada, Kaichiro, Tokai University School of Medicine, Isehara, Japan
  • Komaba, Hirotaka, Tokai University School of Medicine, Isehara, Japan
  • Fukagawa, Masafumi, Tokai University School of Medicine, Isehara, Japan
Background

Podocyte cell death is closely associated with proteinuria-related kidney diseases and the progression of glomerulosclerosis. Transforming growth factor-β1 (TGF-β1) has long been recognized as a key player in the pathogenesis of diabetic kidney disease (DKD). Our previous studies have demonstrated that the cell cycle regulatory protein p21 is involved in this process. However, therapeutic approaches to inhibit this pathway have not been developed.

Methods

To confirm the albuminuria-suppressing effects of active vitamin D, we utilized a streptozotocin-induced diabetic mouse model. These mice were administered paricalcitol, an active form of vitamin D, thrice weekly to observe its effects. In vitro experiments using temperature-sensitive mouse podocytes were conducted to assess TGF-β1-induced cell motility and determine cell cycle regulatory molecule expression. We also investigated the change of these expressions in the presence of active vitamin D. Additionally, we evaluated changes in the expression of vitamin D receptors to examine alterations in signaling pathways in the presence of active vitamin D.

Results

Administration of paricalcitol significantly suppressed albuminuria in the DKD model mice. In cultured podocytes, the increased cell motility induced by TGF-β1 in the scratch assay was inhibited in the presence of paricalcitol. Under these conditions, examination of the expression of cell cycle regulatory proteins revealed that TGF-β1 stimulation led to an increased expression of p21, which was suppressed when paricalcitol was present. Additionally, paricalcitol was found to enhance the mRNA expression of the vitamin D receptor, suggesting a potential positive feedback mechanism in vitamin D signaling in podocytes.

Conclusion

Active vitamin D exerts a protective effect against TGF-β1-induced podocyte injury in DKD, potentially through the suppression of p21 induction.

Funding

  • Government Support – Non-U.S.