Department of Endocrinology, the First Affiliated Hospital, Fujian Medical University, Fuzhou, People's Republic of China.
Department of Endocrinology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, People's Republic of China.
Am J Physiol Regul Integr Comp Physiol. 2024 Oct 1;327(4):R410-R422. doi: 10.1152/ajpregu.00083.2024. Epub 2024 Aug 12.
Inflammation and fibrosis play important roles in diabetic kidney disease (DKD). Previous studies have shown that glucagon-like peptide-1 receptor (GLP-1R) agonists had renal protective effects. However, the mechanisms are not clear. The present study explored the effect of liraglutide (LR), a GLP-1R agonist, on the downregulation of glomerular inflammation and fibrosis in DKD by regulating the Toll-like receptor (TLR)4/myeloid differentiation marker 88 (MyD88)/nuclear factor κB (NF-κB) signaling pathway in mesangial cells (MCs). In vitro, rat MCs were cultured in high glucose (HG). We found that liraglutide treatment significantly reduced the HG-mediated activation of the TLR4/MYD88/NF-κB signaling pathway, extracellular matrix (ECM)-related proteins, and inflammatory factors. A combination of TLR4 inhibitor (TAK242) and liraglutide did not synergistically inhibit inflammatory factors and ECM proteins. Furthermore, in the presence of TLR4 siRNA, liraglutide significantly blunted HG-induced expression of fibronectin protein and inflammatory factors. Importantly, TLR4 selective agonist LPS or TLR4 overexpression eliminated the improvement effects of liraglutide on the HG-induced response. In vivo, administration of liraglutide for 8 wk significantly improved the glomerular damage in streptozotocin-induced diabetic mice and reduced the expression of TLR4/MYD88/NF-κB signaling proteins, ECM protein, and inflammatory factors in renal cortex. TLR4 diabetic mice showed significant amelioration in urine protein excretion rate, glomerular pathological damage, inflammation, and fibrosis. Liraglutide attenuated glomerular hypertrophy, renal fibrosis, and inflammatory response in TLR4 diabetic mice. Taken together, our findings suggest that TLR4/MYD88/NF-κB signaling is involved in the regulation of inflammatory response and ECM protein proliferation in DKD. Liraglutide alleviates inflammation and fibrosis by downregulating the TLR4/MYD88/NF-κB signaling pathway in MCs. Liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), has renoprotective effect in diabetic kidney disease (DKD). In DKD, TLR4/MYD88/NF-κB signaling is involved in the regulation of inflammatory responses and extracellular matrix (ECM) protein proliferation. Liraglutide attenuates renal inflammation and overexpression of ECM proteins by inhibiting TLR4/MYD88/NF-κB signaling pathway. Therefore, we have identified a new mechanism that contributes to the renal protection of GLP-1RA, thus helping to design innovative treatment strategies for diabetic patients with various complications.
炎症和纤维化在糖尿病肾病 (DKD) 中起重要作用。先前的研究表明，胰高血糖素样肽-1 受体 (GLP-1R) 激动剂具有肾脏保护作用。然而，其机制尚不清楚。本研究通过调节肾小球系膜细胞 (MCs) 中的 Toll 样受体 (TLR)4/髓样分化标记物 88 (MyD88)/核因子 κB (NF-κB) 信号通路，探讨了 GLP-1R 激动剂利拉鲁肽对 DKD 中肾小球炎症和纤维化下调的作用。在体外，将大鼠 MCs 培养在高葡萄糖 (HG) 中。我们发现，利拉鲁肽治疗可显著降低 HG 介导的 TLR4/MyD88/NF-κB 信号通路、细胞外基质 (ECM) 相关蛋白和炎症因子的激活。TLR4 抑制剂 (TAK242) 和利拉鲁肽联合使用不能协同抑制炎症因子和 ECM 蛋白。此外，在 TLR4 siRNA 的存在下，利拉鲁肽可显著减弱 HG 诱导的纤连蛋白蛋白和炎症因子的表达。重要的是，TLR4 选择性激动剂 LPS 或 TLR4 过表达消除了利拉鲁肽对 HG 诱导反应的改善作用。在体内，利拉鲁肽治疗 8 周可显著改善链脲佐菌素诱导的糖尿病小鼠的肾小球损伤，并降低肾皮质中 TLR4/MYD88/NF-κB 信号蛋白、ECM 蛋白和炎症因子的表达。TLR4 糖尿病小鼠的尿蛋白排泄率、肾小球病理损伤、炎症和纤维化均有明显改善。利拉鲁肽可减轻 TLR4 糖尿病小鼠的肾小球肥大、肾纤维化和炎症反应。总之，我们的研究结果表明，TLR4/MYD88/NF-κB 信号通路参与了 DKD 中炎症反应和 ECM 蛋白增殖的调节。利拉鲁肽通过下调 MCs 中的 TLR4/MYD88/NF-κB 信号通路减轻炎症和纤维化。利拉鲁肽是胰高血糖素样肽-1 受体激动剂 (GLP-1RA)，对糖尿病肾病 (DKD) 具有肾脏保护作用。在 DKD 中，TLR4/MYD88/NF-κB 信号通路参与了炎症反应和细胞外基质 (ECM) 蛋白增殖的调节。利拉鲁肽通过抑制 TLR4/MYD88/NF-κB 信号通路减轻肾脏炎症和 ECM 蛋白的过度表达。因此，我们确定了一个新的机制，有助于 GLP-1RA 的肾脏保护，从而有助于为有各种并发症的糖尿病患者设计创新的治疗策略。
