Department of Food and Nutrition, Hallym University, Chuncheon, Kangwon-do, 200-702 Korea.
J Agric Food Chem. 2010 Mar 10;58(5):3205-12. doi: 10.1021/jf9040723.
Diabetic nephropathy characterized as mesangial fibrosis and glomerulosclerosis results in renal failure and end-stage renal diseases. Enhanced expression and secretion of connective tissue growth factor (CTGF) play an important role in the expansion of glomerular mesangial matrix mostly composed of type IV collagen. Isoliquiritigenin can prevent various renal injuries via its anti-inflammatory action. However, the effect of isoliquiritigenin on diabetic nephropathy has never been explored. The present study was to investigate whether nontoxic isoliquiritigenin inhibited high glucose (HG)-induced mesangial fibrosis by retarding formation of type IV collagen as well as CTGF in human mesangial cells (HRMC). Serum starved cells were cultured in media containing 5.5 mM glucose plus 27.5 mM mannitol as an osmotic control or 33 mM glucose for 3 days with and without 1-20 microM isoliquiritigenin. Exposure of cells to HG caused marked increases in collagen secretion and CTGF expression, which was dose-dependently reversed by isoliquiritigenin at the transcriptional levels. Additionally, isoliquiritigenin boosted HG-plummeted type matrix metalloproteinase-1 (MT-1 MMP) expression and dampened HG-elevated tissue inhibitor of MMP-2 (TIMP-2) expression, facilitating the degradation of mesangial matrix. Isoliquiritigenin inhibited HG-upregulated CTGF and TIMP-2 expression via disturbing TGF-beta1 signaling in HRMC, as evidenced by TGF-beta receptor I kinase (TGF-beta RI) inhibitor. HG-activated SMAD2 through autocrine TGF-beta signaling was repealed by > or =10 microM isoliquiritigenin. HG induced SMAD4 expression of HRMC and obliterated antagonistic SMAD7, whereas isoliquiritigenin suppressed induction of TGF-beta RII and TGF-beta RI with blunting their downstream SMAD signaling. The results demonstrate that the bioactive isoliquiritigenin in licorice diminished mesangial matrix accumulation in response to ambient HG through retarding TGF-beta1-SMAD signaling transduction. Therefore, isoliquiritigenin may be a potential therapeutic agent for the prevention and treatment of mesangial fibrosis and glomerulosclerosis leading to diabetic nephropathy due to longstanding diabetes mellitus.
糖尿病肾病的特征是系膜纤维化和肾小球硬化，导致肾衰竭和终末期肾病。结缔组织生长因子 (CTGF) 的高表达和分泌在肾小球系膜基质的扩张中起重要作用，系膜基质主要由 IV 型胶原组成。甘草素可以通过抗炎作用预防各种肾脏损伤。然而，甘草素对糖尿病肾病的作用从未被探索过。本研究旨在探讨非毒性甘草素是否通过延缓 IV 型胶原和 CTGF 在人肾小球系膜细胞 (HRMC) 中的形成来抑制高葡萄糖 (HG) 诱导的系膜纤维化。将饥饿的细胞在含有 5.5 mM 葡萄糖加 27.5 mM 甘露醇的培养基中培养，作为渗透压对照，或在 33 mM 葡萄糖中培养 3 天，同时加入 1-20 μM 甘草素。细胞暴露于 HG 导致胶原分泌和 CTGF 表达显著增加，甘草素在转录水平上呈剂量依赖性逆转。此外，甘草素上调了 HG 降低的基质金属蛋白酶-1 (MT-1 MMP) 表达，降低了 HG 升高的基质金属蛋白酶抑制剂-2 (TIMP-2) 表达，促进了系膜基质的降解。甘草素通过干扰 HRMC 中的 TGF-β1 信号通路抑制 HG 上调的 CTGF 和 TIMP-2 表达，这一点可以通过 TGF-β 受体 I 激酶 (TGF-β RI) 抑制剂得到证明。HG 通过自分泌 TGF-β 信号激活 SMAD2，而 >或=10 μM 甘草素则使其失活。HG 诱导 HRMC 的 SMAD4 表达，并消除拮抗 SMAD7，而甘草素抑制 TGF-β RII 和 TGF-β RI 的诱导，并减弱其下游 SMAD 信号转导。结果表明，甘草中的生物活性成分甘草素通过延缓 TGF-β1-SMAD 信号转导，减少了对环境 HG 的系膜基质堆积。因此，甘草素可能是预防和治疗糖尿病肾病导致的系膜纤维化和肾小球硬化的潜在治疗剂。
