Department of TCMs Pharmaceuticals & Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, PR China.
Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, PR China.
Food Funct. 2022 May 23;13(10):5536-5546. doi: 10.1039/d1fo02445k.
Diabetic nephropathy (DN) fibrosis is a major cause of end-stage renal disease with unsatisfactory therapy drugs and a low 5-year survival rate. There is a lack of specific and effective treatment drugs. In the present study, we report that asiatic acid (AA), a triterpenic acid found in , has good anti-fibrosis activity both and . The STZ-induced diabetic model of rats was used to investigate the effects of AA on DN fibrosis. A 15-week AA treatment (10 mg kg or 30 mg kg) markedly decreased urine albumin and blood urea nitrogen levels, and ameliorated increased mesangial matrix and glomerular fibrosis. HG + TGF-β1-induced HK-2 cells were applied to evaluate the anti-fibrosis effect of AA. The results revealed AA selectively blocked the interaction of TGF-β type I receptor (TGF-βRI) with Smad3 by binding to TGF-βRI, suppressed the subsequent phosphorylation and nuclear translocation of Smad3, and downregulated the major fibrotic protein expression of collagen I, fibronectin and a-smooth muscle actin (α-SMA), thereby switching the progress of epithelial-mesenchymal transition (EMT). Furthermore, the protein levels of LC3 and LAMP1 were significantly altered by AA administration, implying that the autophagy-lysosome system might be involved in DN fibrosis. However, the anti-fibrosis capacity of AA was partly counteracted by an autophagy-lysosome inhibitor (chloroquine). These findings indicate AA could decrease TGF-β1 secretion and suppress tubulointerstitial fibrosis by directly inhibiting TGF-βR1 and activating the autophagy-lysosome system. Altogether, AA may be a potential candidate drug for preventing DN fibrosis.
糖尿病肾病（DN）纤维化是终末期肾病的主要原因，治疗药物不理想，5 年生存率低。缺乏特异性和有效的治疗药物。在本研究中，我们报告，齐墩果酸（AA），一种在 中发现的三萜酸，具有良好的抗纤维化活性 和 。使用链脲佐菌素（STZ）诱导的糖尿病大鼠模型研究 AA 对 DN 纤维化的影响。15 周的 AA 治疗（10mg/kg 或 30mg/kg）显著降低尿白蛋白和血尿素氮水平，并改善了系膜基质和肾小球纤维化的增加。应用高糖（HG）+转化生长因子-β1（TGF-β1）诱导的人近端肾小管上皮细胞（HK-2 细胞）来评估 AA 的抗纤维化作用。结果表明，AA 通过与 TGF-βRI 结合选择性阻断 TGF-β Ⅰ型受体（TGF-βRI）与 Smad3 的相互作用，抑制 Smad3 的后续磷酸化和核转位，并下调胶原 I、纤连蛋白和α-平滑肌肌动蛋白（α-SMA）等主要纤维化蛋白的表达，从而改变上皮-间充质转化（EMT）的进程。此外，AA 给药显著改变了 LC3 和 LAMP1 的蛋白水平，表明自噬溶酶体系统可能参与了 DN 纤维化。然而，自噬溶酶体抑制剂（氯喹）部分抵消了 AA 的抗纤维化能力。这些发现表明，AA 可以通过直接抑制 TGF-βR1 和激活自噬溶酶体系统来减少 TGF-β1 的分泌并抑制肾小管间质纤维化。总的来说，AA 可能是预防 DN 纤维化的潜在候选药物。
