Abstract: TH-PO1120
Sabizabulin Ameliorates Kidney Fibrosis by Inhibition of Myofibroblast-Specific Beta Tubulin 3
Session Information
- CKD: Mechanisms - 1
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Ikeda, Yoichiro, Tokyo Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Bunkyo-ku, Tokyo, Japan
- Nangaku, Masaomi, Tokyo Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Bunkyo-ku, Tokyo, Japan
Background
Tubulointerstitial fibrosis is the hallmark of pathological changes found in the kidneys of CKD patients irrespective of the etiologies. A variety of investigations have been conducted to elucidate the mechanisms of progression to CKD to end-stage kidney diseases so far, but still substantially effective remedies to prevent CKD are limited and not clinically applied.
Beta tubulin3 (TUBB3) is specifically expressed in neurons in normal settings, but we found that it is expressed specifically in interstitial cells in kidneys with tubulointerstitial fibrosis. Then we investigated if the intervention of expression of TUBB3 affects the tubulointerstitial fibrosis in kidney in the setting of CKD by using TUBB3-specific inhibitor sabizabulin.
Methods
10T1/2 cells and mouse primary fibroblasts were used for the fibrogenic assays in vitro by an addition of TGF-beta. Standard C57BL/6 mice were used for the analysis in vivo by doing unilateral ureteral obstruction (UUO) under treatments with TUBB3 inhibitor sabizabulin or vehicle.
Results
Mouse primary fibroblasts, considered as a model of fibroblasts or pericytes, expressing low levels of TUBB3 at baseline, increase fibrogenic responses when stimulated by TGFb, and TUBB3 inhibitor significantly reduced their responses. (aSMA reduction by 40%) Knockdown of TUBB3 by siRNA also showed its significant reduction. (aSMA reduction by 60%) 10T1/2 cells, considered as a model of myofibroblasts, express high levels of TUBB3 at base line, and show strong fibrogenic phenotypes. Sabizabulin reduces fibrogenic responses significantly in a dose dependent manner. (aSMA reduction by up to 70%)
UUO mice develop kidney fibrosis in the kidney with a ligation in a time dependent manner. TUBB3 expression is significantly elevated accordingly by UUO, and TUBB3 inhibitor successfully reduced the total TUBB3 expression in UUO kidney in a dose dependent manner. (up to 70%) Surprisingly, histological changes in UUO were significantly suppressed by sabizabulin. Fibrogenic responses were also attenuated by sabizabulin (aSMA reduction by 50%)
Conclusion
Sabizabulin was shown to be effective to ameliorate kidney fibrosis in virto and in vivo. It could be a potential treatment option for CKD.
Funding
- Government Support – Non-U.S.