874-P: Potential Anti-Inflammatory Effects of Canagliflozin in Tumour Necrosis Factor-α and Interferon-ϒ-Stimulated Endothelial Cells

Abstract

Background: This study investigates the potential direct anti-inflammatory effects of the SGLT2 inhibitors (canagliflozin, C; dapagliflozin D; or empagliflozin, E) on cultured endothelial cells. Methods: Human umbilical vein endothelial cells (HUVECs) or Human cardio microvascular endothelial cells (HCMECs) were pre-incubated in the presence or absence of C (0.5μM, 1μM, and 10μM) , D (0.5μM, 1μM, and 10μM) and E (0.5μM, 1μM, and 10μM) for 1 hr and NaCl (150 mM) for 24 hr. The cells were then stimulated with TNF-α (ng/mL) and IFN-Υ (ng/mL) for 24 hrs. Expression of IL-6 and was analysed using Quantikine ELISA kits. The expression of SGLT2 mRNA was assessed using RT-PCR in cDNA prepared from two independent cultures of HUVECs and HCMECs using cDNA from human kidney cortex as a positive control. Results: TNF-α and IFN-Υ and significantly induced expression of IL-6 in both HUVECs and HCMECs compared to controls (p = <0.0001) . The effects were significantly inhibited by canagliflozin 0.1μM, 1μM, and 10μM (p=0.0099, p< 0.0001, and p<0.0001, respectively) in HUVECs. In HCMECs, C, (0.5μM, 1μM, and 10μM) significantly inhibit the TNF-α and IFN-Υ IL-6 secretion (p< 0.0001, p< 0.0001, and p<0.0001, respectively) . No significant effect of D and E was observed. High NaCl had no influence on C (0.5μM, 1μM, and 10μM) inhibition of TNF-α and IFN-Υ induced of IL-6 secretion, and high salt alone had no influence on the secretion of IL-6 secretion. SGLT2 mRNA levels were below the detection level in HUVECs and HCMECs alone and on high glucose and TNF-α and IFN-Υ conditions. Conclusion: This result indicates that SGLT2-I directly inhibits endothelial pro-inflammatory cytokines secretions. This striking anti-inflammatory of the SGLT2 inhibitor class merits further mechanistic research. Disclosure A.S.Alshnbari: None. R.N.Khan: None. I.R.Idris: None.