Department of Nephropathy, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, PR China.
Department of Nephropathy, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, PR China; Center for Scientific Research of Anhui Medical University, Hefei, Anhui 230022, PR China.
Biomed Pharmacother. 2024 Nov;180:117499. doi: 10.1016/j.biopha.2024.117499. Epub 2024 Sep 30.
Diabetic nephropathy (DN) is one of the serious microvascular complications of diabetes mellitus. During the progression of DN, the proliferation of glomerular mesangial cells (GMCs) leads to the deposition of excessive extracellular matrix (ECM) in the mesangial region, eventually resulting in glomerulosclerosis. Rutaecarpine (Rut), an alkaloid found in the traditional Chinese medicinal herb Fructus Evodiae (Euodia rutaecarpa (Juss.) Benth.), has many biological activities. However, its mechanism of action in DN remains unknown. This study used db/db mice and high glucose (HG)-treated mouse mesangial cells (SV40 MES-13) to evaluate the protective effects of Rut and underlying mechanisms on GMCs in DN. We found that Rut alleviated urinary albumin and renal function and significantly relieved renal pathological damage. In addition, Rut decreased the ECM production, and renal inflammation and suppressed the activation of TGF-β1/Smad3 and NF-κB signaling pathways in vitro and in vivo. Protein kinase CK2α (CK2α) was identified as the target of Rut by target prediction, molecular docking, and cellular thermal shift assay (CETSA), and surface plasmon resonance (SPR). Furthermore, Rut could not continue to play a protective role in HG-treated SV40 cells after silencing CK2α. In summary, this study is the first to find that Rut can suppress ECM production and inflammation in HG-treated SV40 cells by inhibiting the activation of TGF-β1/Smad3 and NF-κB signaling pathways and targeting CK2α. Thus, Rut can potentially become a novel treatment option for DN.
糖尿病肾病（DN）是糖尿病严重的微血管并发症之一。在 DN 的进展过程中，肾小球系膜细胞（GMC）的增殖导致细胞外基质（ECM）在系膜区过度沉积，最终导致肾小球硬化。吴茱萸碱（Rut）是一种存在于传统中药吴茱萸（Euodia rutaecarpa (Juss.) Benth.）中的生物碱，具有多种生物活性。然而，其在 DN 中的作用机制尚不清楚。本研究采用 db/db 小鼠和高糖（HG）处理的小鼠系膜细胞（SV40 MES-13），评估 Rut 对 DN 中 GMC 的保护作用及其潜在机制。我们发现 Rut 可减轻尿白蛋白和肾功能，并显著缓解肾脏病理损伤。此外，Rut 减少 ECM 的产生、肾脏炎症，并抑制 TGF-β1/Smad3 和 NF-κB 信号通路的激活，无论是在体外还是体内。蛋白激酶 CK2α（CK2α）是通过靶标预测、分子对接和细胞热转移分析（CETSA）以及表面等离子体共振（SPR）鉴定出的 Rut 的靶标。此外，沉默 CK2α 后，Rut 不能继续在 HG 处理的 SV40 细胞中发挥保护作用。总之，本研究首次发现 Rut 通过抑制 TGF-β1/Smad3 和 NF-κB 信号通路的激活和靶向 CK2α，可抑制 HG 处理的 SV40 细胞中 ECM 的产生和炎症。因此，Rut 可能成为治疗 DN 的一种新方法。
