Zhang Chenzhu, Tam Tsz Wai, Chau Mel Km, García Córdoba Cristina Alexandra, Yung Susan, Chan Tak Mao
Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China.
Front Pharmacol. 2022 Apr 28;13:866077. doi: 10.3389/fphar.2022.866077. eCollection 2022.
A significant proportion of lupus nephritis patients develop chronic kidney disease (CKD) and progressive kidney fibrosis, for which there is no specific treatment. We previously reported that mycophenolate or rapamycin monotherapy showed comparable efficacy in suppressing kidney fibrosis in a murine model of lupus nephritis through their direct action on mesangial cells. We extended our study to investigate the effect of combined mycophenolate and rapamycin treatment (MR) on kidney fibrosis in NZBWF1/J mice. Female NZBWF1/J mice with active nephritis were randomized to receive vehicle or treatment with mycophenolate (50 mg/kg/day) and rapamycin (1.5 mg/kg/day) (MR) for up to 12 weeks, and the effect of treatment on clinical parameters, kidney histology, and fibrotic processes was investigated. Progression of nephritis in untreated mice was accompanied by mesangial proliferation, glomerulosclerosis, tubular atrophy, protein cast formation, increased mTOR and ERK phosphorylation, and induction of TGF-β1, IL-6, α-smooth muscle actin, fibronectin, and collagen expression. Combined MR treatment prolonged survival, improved kidney function, decreased anti-dsDNA antibody level, and ameliorated histopathological changes. The effect of combined MR treatment on kidney histology and function was comparable to that of mycophenolate or rapamycin monotherapy. studies in human mesangial cells showed that exogenous TGF-β1 and IL-6 both induced mTOR and ERK phosphorylation and downstream fibrotic processes. Both mycophenolic acid and rapamycin inhibited inflammatory and fibrotic processes induced by TGF-β1 or IL-6 by downregulating mTOR and ERK phosphorylation. Our findings indicate that combined mycophenolate and rapamycin, at reduced dose, improves kidney fibrosis in murine lupus nephritis through their distinct effect on mTOR and ERK signaling in mesangial cells.
相当一部分狼疮性肾炎患者会发展为慢性肾脏病（CKD）和进行性肾纤维化，对此尚无特异性治疗方法。我们之前报道过，霉酚酸酯或雷帕霉素单药治疗在狼疮性肾炎小鼠模型中通过对系膜细胞的直接作用，在抑制肾纤维化方面显示出相当的疗效。我们扩展了研究，以探究霉酚酸酯与雷帕霉素联合治疗（MR）对NZBWF1/J小鼠肾纤维化的影响。将患有活动性肾炎的雌性NZBWF1/J小鼠随机分为接受赋形剂或用霉酚酸酯（50毫克/千克/天）和雷帕霉素（1.5毫克/千克/天）进行治疗（MR），持续长达12周，并研究治疗对临床参数、肾脏组织学和纤维化过程的影响。未治疗小鼠的肾炎进展伴有系膜增生、肾小球硬化、肾小管萎缩、蛋白管型形成、mTOR和ERK磷酸化增加，以及TGF-β1、IL-6、α-平滑肌肌动蛋白、纤连蛋白和胶原蛋白表达的诱导。联合MR治疗延长了生存期，改善了肾功能，降低了抗双链DNA抗体水平，并改善了组织病理学变化。联合MR治疗对肾脏组织学和功能的影响与霉酚酸酯或雷帕霉素单药治疗相当。在人系膜细胞中的研究表明，外源性TGF-β1和IL-6均诱导mTOR和ERK磷酸化以及下游纤维化过程。霉酚酸和雷帕霉素均通过下调mTOR和ERK磷酸化来抑制由TGF-β1或IL-6诱导的炎症和纤维化过程。我们的研究结果表明，较低剂量的霉酚酸酯与雷帕霉素联合使用，通过对系膜细胞中mTOR和ERK信号通路的不同作用，改善了小鼠狼疮性肾炎的肾纤维化。
