Department of Medicine, The University of Hong Kong, The University of Hong Kong, Hong Kong.
Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
Clin Sci (Lond). 2019 Aug 5;133(15):1721-1744. doi: 10.1042/CS20190536. Print 2019 Aug 15.
Lupus nephritis (LN) leads to chronic kidney disease (CKD) through progressive fibrosis. Mycophenolate inhibits inosine monophosphate dehydrogenase and is a standard treatment for LN. The mammalian or mechanistic target of rapamycin (mTOR) pathway is activated in LN. Rapamycin inhibits mTOR and is effective in preventing kidney transplant rejection, with the additional merits of reduced incidence of malignancies and viral infections. The effect of mycophenolate or rapamycin on kidney fibrosis in LN has not been investigated. We investigated the effects of mycophenolate and rapamycin in New Zealand Black and White first generation (NZB/W F1) murine LN and human mesangial cells (HMCs), focusing on mechanisms leading to kidney fibrosis. Treatment of mice with mycophenolate or rapamycin improved nephritis manifestations, decreased anti-double stranded (ds) DNA antibody titer and reduced immunoglobulin G (IgG) deposition in the kidney. Both mycophenolate and rapamycin, especially the latter, decreased glomerular mTOR Ser phosphorylation. Renal histology in untreated mice showed mesangial proliferation and progressive glomerulosclerosis with tubular atrophy, and increased expression of transforming growth factor β1 (TGF-β1), monocyte chemoattractant protein-1 (MCP-1), α-smooth muscle actin (α-SMA), fibronectin (FN) and collagen. Both mycophenolate and rapamycin ameliorated the histopathological changes. Results from experiments showed that both mycophenolate and rapamycin decreased mesangial cell proliferation and their binding with anti-dsDNA antibodies. Mycophenolate and rapamycin also down-regulated mTOR and extracellular signal-regulated kinase (ERK) phosphorylation and inhibited fibrotic responses in mesangial cells that were induced by anti-dsDNA antibodies or TGF-β1. Our findings suggest that, in addition to immunosuppression, mycophenolate and rapamycin may reduce fibrosis in LN, which has important implications in preventing CKD in patients with LN.
狼疮性肾炎 (LN) 通过进行性纤维化导致慢性肾脏病 (CKD)。霉酚酸酯抑制肌苷单磷酸脱氢酶，是 LN 的标准治疗方法。哺乳动物雷帕霉素靶蛋白（mTOR）途径在 LN 中被激活。雷帕霉素抑制 mTOR，在预防肾移植排斥方面有效，并且具有降低恶性肿瘤和病毒感染发生率的额外优点。霉酚酸酯或雷帕霉素对 LN 肾纤维化的影响尚未得到研究。我们研究了霉酚酸酯和雷帕霉素在新西兰黑白色第一代（NZB/W F1）狼疮性肾炎小鼠和人肾小球系膜细胞（HMC）中的作用，重点研究导致肾脏纤维化的机制。用霉酚酸酯或雷帕霉素治疗小鼠可改善肾炎表现，降低抗双链 (ds) DNA 抗体滴度并减少肾脏中 IgG 沉积。霉酚酸酯和雷帕霉素均能降低肾小球 mTOR Ser 磷酸化，尤其是后者。未经治疗的小鼠的肾脏组织学显示系膜增生和进行性肾小球硬化伴肾小管萎缩，并增加转化生长因子β1 (TGF-β1)、单核细胞趋化蛋白-1 (MCP-1)、α-平滑肌肌动蛋白 (α-SMA)、纤维连接蛋白 (FN) 和胶原蛋白的表达。霉酚酸酯和雷帕霉素均改善了组织病理学变化。实验结果表明，霉酚酸酯和雷帕霉素均可降低系膜细胞增殖及其与抗 dsDNA 抗体的结合。霉酚酸酯和雷帕霉素还可下调 mTOR 和细胞外信号调节激酶 (ERK) 的磷酸化，并抑制抗 dsDNA 抗体或 TGF-β1 诱导的系膜细胞的纤维化反应。我们的研究结果表明，除免疫抑制作用外，霉酚酸酯和雷帕霉素还可能减少 LN 中的纤维化，这对预防 LN 患者的 CKD 具有重要意义。
