National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
Department of Pharmacological Sciences, Mount Sinai Center for Bioinformatics, BD2K-LINCS Data Coordination and Integration Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Kidney Int. 2018 Feb;93(2):416-429. doi: 10.1016/j.kint.2017.08.031.
A recent clinical study showed that combination therapy consisting of mycophenolate mofetil, tacrolimus and steroids was shown to be more effective in achieving complete remission in patients with severe forms of lupus nephritis than conventional therapy consisting of intravenous cyclophosphamide and steroids. To explore the underlying molecular and cellular mechanisms of increased efficacy of the combination therapy regimen, we employed a mouse model of lupus nephritis, MRL/lpr mice, and treated them with monotherapies of prednisone, mycophenolate mofetil, or tacrolimus, or with their combination. Consistent with previous clinical findings, combination therapy markedly improved renal outcome compared to the monotherapies in mice with lupus nephritis. Transcriptomic analysis of their kidneys revealed distinct molecular pathways that were differentially regulated in combination therapy versus monotherapies. Combination therapy not only provided additive immunosuppressive effects, but also induced gene expression and molecular pathways to confer enhanced renoprotection. Specifically, combination therapy inhibited TLR7 expression in the kidneys of mice with lupus nephritis; combination of tacrolimus and mycophenolate mofetil led to better stabilization of the podocyte actin cytoskeleton through the reciprocal regulation of RhoA and Rac1 activities. Combination therapy strongly suppressed the IL-6/Stat3 pathway. These findings were further validated in renal biopsy samples from patients with lupus nephritis before and after treatments with mycophenolate mofetil, tacrolimus or combination therapy. Thus, our study further supports the earlier clinical finding and further provides insights into the molecular basis for increased efficacy of combination therapy.
最近的一项临床研究表明，与包含环磷酰胺和类固醇的传统疗法相比，霉酚酸酯、他克莫司和类固醇联合治疗可更有效地使狼疮性肾炎重症患者达到完全缓解。为了探究联合治疗方案疗效提高的潜在分子和细胞机制，我们采用狼疮肾炎 MRL/lpr 小鼠模型，并用泼尼松、霉酚酸酯或他克莫司单药治疗，或联合治疗。与之前的临床发现一致，联合治疗与狼疮肾炎小鼠的单药治疗相比，明显改善了肾脏结局。对其肾脏的转录组分析揭示了联合治疗与单药治疗相比差异调节的不同分子途径。联合治疗不仅提供了附加的免疫抑制作用，而且诱导了基因表达和分子途径，以增强肾脏保护作用。具体而言，联合治疗抑制了狼疮肾炎小鼠肾脏中 TLR7 的表达；他克莫司和霉酚酸酯的联合使用通过 RhoA 和 Rac1 活性的相互调节，导致足细胞肌动蛋白细胞骨架更好地稳定。联合治疗强烈抑制了 IL-6/Stat3 途径。这些发现进一步在狼疮肾炎患者肾活检样本中得到了验证，这些患者在接受霉酚酸酯、他克莫司或联合治疗前后进行了治疗。因此，我们的研究进一步支持了早期的临床发现，并进一步深入了解了联合治疗疗效提高的分子基础。
