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.
A.S.Alshnbari: None. R.N.Khan: None. I.R.Idris: None.