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Abstract: FR-PO354

Canagliflozin Greatly Improves Mitochondrial Stress Response in Proximal Tubular Cells (PTCs) of Mice with Combined Hypertension and Type 1 Diabetes

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Trentin Sonoda, Mayra, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
  • Cheff, Veronique, University of Ottawa, Ottawa, Ontario, Canada
  • Burelle, Yan, University of Ottawa, Ottawa, Ontario, Canada
  • Hebert, Richard L., University of Ottawa, Ottawa, Ontario, Canada
Background

Canagliflozin (CANA) is a sodium-glucose cotransporter 2 (SGLT2) inhibitor with blood glucose lowering effects. CANA promotes kidney protection in patients with type 2 diabetes (T2D), as well as cardiovascular complications. Both diabetes and hypertension induce mitochondrial dysfunction and oxidative stress. However, it is still unclear whether CANA modulates mitochondrial function in diabetic kidney diseases.

Methods

In vivo: Male and female 8 weeks old genetic hypertensive mice (Lin) were subjected to daily intraperitoneal injections of streptozotocin (STZ) for 5 days. 4 weeks after the STZ injections, mice were fed either regular or CANA-infused diet for 1 week. Urinary albumin levels were determined by ELISA and urinary creatinine by colorimetric assay. Proximal tubular epithelial cells (PTCs) isolated from experimental mice were subjected to Seahorse MitoStress test. Kidney OXPHOS complexes were analyzed by Western blotting. In vitro: PTCs were isolated from Fvb mice, treated with 100nM Ang II + 30mM glucose for 24h, followed by treatment with 10uM CANA or vehicle for 24h.

Results

Male and females LinSTZ mice had elevated albumin to creatinine ratio (ACR), while CANA reverted the ACR increase in males (23,578 ± 7,937 vs 3,014 ± 492.5, n=4, P<0.05) and females (6,758 ± 906.8 vs 623.4 ± 103.8, n=3, P<0.01). Overall, PTCs from LinSTZ + CANA greatly improved oxygen consumption rate (OCR) throughout the mitochondrial stress test (P<0.0001), with significant increase in OCR after inhibition of complexes I, II, and V in males (n=4, P<0.05) and females (n=3, P<0.05). A trend to decrease protein levels of OXPHOS complexes were also observed in the kidney of LinSTZ + CANA mice (n=2-3, P>0.08). In vitro, CANA overall effect on OCR was more pronounced in males, whereas in females there was a higher response to the disruption of mitochondrial oxidative phosphorylation by FCCP (P<0.001).

Conclusion

Canagliflozin promoted kidney protection, shown by improvement of albuminuria in hypertensive-diabetic mice. Moreover, we show evidence of improved mitochondria function induced by CANA in vivo and in vitro. Besides the benefits related to restoration of glucose homeostasis, CANA could play a role on proximal tubular mitochondrial function and remodeling.

Funding

  • Private Foundation Support