Empagliflozin alleviates renal inflammation in Sprague Dawley diabetic rats by inhibiting TLR4 / NF-κB pathway and NLRP3 inflammasome activation

Abstract Aims To investigate the potential effects of the SGLT2 inhibitor empagliflozin on renal inflammatory pathways in diabetic rats. Materials and Methods Sprague Dawley (SD) diabetic rats model was established by intraperitoneal injection of streptozotocin (STZ, 35 mg/kg) after 4-week high-sugar and high-fat diet intervention. Rats were randomly assigned to three groups: normal control (NC), diabetes with normal saline (DM + NS), and diabetes with empagliflozin (DM + EMP). Empagliflozin (10mg/kg/day) or equivalent volume of normal saline was administered to the appropriate group. After 4 weeks intervention, the rats were euthanized, and kidney tissues were obtained. The mRNA transcription levels of TLR4, NF-κB, NLRP3, IL-1β, IL-18, caspase-1, caspase-3, and TGF-β1 were assessed using the RT-qPCR. Additionally, Western blot analysis was conducted to determine TLR4, NF-κB, NLRP3 and IL-18 protein expression levels in the rat kidneys. Results Compared to the DM + NS group, the mRNA levels of TLR4, NF-κB, NLRP3, and IL-18 were significantly decreased in the DM + EMP group, TLR4[1.02 (0.32, 2.66) vs. 0.17(0.06, 0.27), P = 0.022], NF-κB[1.38 (1.12, 2.05) vs. 0.82(0.69, 1.00), P = 0.002], and NLRP3[0.60 (0.13, 0.93) vs. 0.04(0.03, 0.18), P = 0.025], IL-18[1.66(1.50, 1.76) vs. 6.68(2.17, 11.16), P = 0.002], respectively. The mRNA levels of IL-1β, caspase-1, caspase-3, and TGF-β1 were demonstrated a significant decrease, but did not reach statistical significance. Empagliflozin attenuated the protein expression of TLR4, NF-κB, NLRP3 and IL-18, which seem to restore to near normal control levels. Conclusion Our research suggests that empagliflozin may exert anti-inflammatory effects in the kidney tissue by inhibiting the TLR4/NF-κB axis activation and the priming of NLRP3 inflammasome.