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Abstract: SA-PO436

Canagliflozin Inhibits Hedgehog Interacting Protein (Hhip)-Mediated Renal Tubular Cell Senescence in Type 1 Akita Mice

Session Information

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
  • Miyata, Kana N., 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
  • Zhao, Xin-Ping, 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., Massachusetts General Hospital, 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 have recently reported that hedgehog interacting protein (Hhip) activates sodium-glucose cotransporter 2 (Sglt2) expression and promotes tubular senescence-associated secretory phenotype (SASP) in murine diabetic kidney disease (DKD) (Diabetiologia 2023). However, the underlying mechanism(s) are poorly understood. Here, we aimed to elucidate the functional impact of the SGLT2 inhibitor, Canagliflozin (Cana) on tubular Hhip-mediated cell senescence in vivo and in vitro.

Methods

Akita renal proximal tubular cells (RPTC)-specific Hhip transgenic (Tg) mice (Akita/Hhip-Tg), Akita/non-Tg and their respective controls (Hhip-Tg or non-Tg) were studied. Cana was administered to Akita mice (Akia/Hhip-Tg vs. Akia/non-Tg) in water (10 or 30 mg/kg/day) from 6 to 20 weeks of age. Primary RPTCs and rat immortalized RPTC cells (IRPTCs) were also employed.

Results

Hhip-Tg mice were fertile and phenotypically normal cf. non-Tg. Compared to respective controls at 20-weeks, both Akita/Hhip-Tg and Akita/non-Tg mice displayed typical DKD dysfunction (hypertension, hyperglycemia, polyuria, increased urinary albumin/creatinine ratio and glomerular filtration rate) and dysmorphology (renal hypertrophy, glomerulosclerosis and tubulopathy). These features were more pronounced in Akia/Hhip-Tg than in Akita/non-Tg. Cana administration ameliorated DKD features in a dose-dependent manner. There was evidence of renal tubular SASP--Heightened β-galactosidase activity was seen in Hhip-Tg cf. non-Tg mice, and its activity was more pronounced in Akita/Hhip-Tg cf. Akita/non-Tg mice. In contrast, Cana more effectively inhibited tubular SASP in kidneys of Akita/non-Tg cf. Akita/Hhip-Tg mice. In IRPTCs, excessive Hhip gene expression through either engineered overexpression or high glucose (25mM D-glucose) stimulation promoted extracellular vehicle (apoptotic bodies and microvesicles)-mediated cellular senescence, and their effects were inhibited by the addition of canagliflozin (500nM).

Conclusion

Canagliflozin appears to be capable of offsetting DKD-related tubulopathy and tubular senescence, possibly, via the inhibition of excessive Hhip delivered extracellularly in DKD.

Funding

  • Government Support – Non-U.S.