Spleen tyrosine kinase promotes NLR family pyrin domain containing 3 inflammasome-mediated IL-1β secretion via c-Jun N-terminal kinase activation and cell apoptosis during diabetic nephropathy

Diabetic nephropathy (DN) is a serious complication of diabetes and can cause an increased mortality risk. It was previously reported that NLR family pyrin domain containing 3 (NLRP3) inflammasome is involved in the pathogenesis of diabetes. However, the underlying mechanism is not clearly understood. In the present study, the effects of spleen tyrosine kinase (Syk) and c-Jun N-terminal kinase (JNK) on the NLRP3 inflammasome were examined in vivo and in vitro. Sprague-Dawley rats were injected intraperitoneally with streptozotocin (65 mg/kg) to induce diabetes. HK2 cells and rat glomerular mesangial cells (RGMCs) were examined to detect the expression of JNK and NLRP3 inflammasome-associated proteins following treatment with a Syk inhibitor or Syk-small interfering (si)RNA in a high glucose condition. In the present study, it was revealed that the protein and mRNA expression levels of NLRP3 inflammasome-associated molecules and the downstream mature interleukin (IL)-1β were upregulated in vivo and in vitro. The Syk inhibitor and Syk-siRNA suppressed high glucose-induced JNK activation, and subsequently downregulated the activation of the NLRP3 inflammasome and mature IL-1β in HK2 cells and RGMCs. Furthermore, high glucose-induced apoptosis of HK2 cells was reduced by the Syk inhibitor BAY61-3606. Therefore, the present results determined that high glucose-induced activation of the NLRP3 inflammasome is mediated by Syk/JNK activation, which subsequently increased the protein expression level of IL-1β and mature IL-1β. The present study identified that the Syk/JNK/NLRP3 signaling pathway may serve a vital role in the pathogenesis of DN.