Abstract: SA-PO258
Senolytics (Dasatinib/Quercetin) Inhibit Hedgehog Interacting Protein (Hhip)-Mediated Tubular Senescence in Diabetic Kidney Disease
Session Information
- Diabetic Kidney Disease: Basic - 2
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Chang, Shiao-Ying, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
- Liao, Min-Chun, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
- Pang, Yuchao, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
- Peng, Junzheng, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
- Ingelfinger, Julie R., Harvard Medical School, Boston, Massachusetts, United States
- Chan, John S.D., Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
- Zhang, Shao-Ling, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada
Background
We recently reported that hedgehog interacting protein (Hhip) promotes tubular senescence-associated secretory phenotype in murine diabetic kidney disease (DKD) (Diabetiologia, 2023), the underlying mechanism(s) are not delineated. Here, we asked whether senolytics (dasatinib, D/quercetin, Q) could alleviate Hhip-mediated RPTC senescence in DKD in vivo and in vitro
Methods
The low-dose streptozotocin (LDSTZ)-induced diabetes in renal proximal tubules (RPTC)-specific Hhip transgenic (Tg) mice (Hhip-Tg) and their non-Tg littermates at the age of 10-week old were studied. Senolytics (D, 5 mg/kg and Q, 50 mg/kg) in combination were administered by gavage daily for three consecutive days every two weeks from 12 weeks until the mice were 24-weeks old. Vehicle-treated animals served as controls. Primary RPTCs and rat immortalized RPTC cells (IRPTCs) were used for in vitro studies.
Results
Diabetic mice displayed typical DKD characteristics (hyperglycemia, increased urinary albumin/creatinine ratio and glomerular filtration rate) and renal dysmorphology (renal hypertrophy, glomerulosclerosis and tubulopathy), and those features were more pronounced in diabetic Hhip-Tg (vs. non-Tg) mice. D/Q senolytics administration ameliorated DKD dysmorphology and renal tubular senescence as measured by heightened β-galactosidase activity in kidneys of diabetic mice. In vitro, excessive Hhip induced by overexpressing Hhip in RPTCs triggered the release of extracellular vesicles carrying Hhip, which facilitated RPTC turnover through accelerated cellular senescence, and fibrotic and apoptotic processes. In contrast, D/Q treatment reversed the effects of increased Hhip in RPTCs.
Conclusion
The treatment of senolytic D/Q prevents excessive Hhip-mediated RPTC senescence and DKD-related tubulopathy via the inhibition of Hhip carried by extracellular vehicles in DKD.
Funding
- Government Support – Non-U.S.