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Kidney Int. 2018 Feb;93(2):416-429. doi: 10.1016/j.kint.2017.08.031.

Transcriptomic analysis uncovers novel synergistic mechanisms in combination therapy for lupus nephritis.

Author information

1
National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
2
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.
3
Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
4
Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Department of Nephrology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China.
5
Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Renal Program, James J Peters VA Medical Center, Bronx, New York, USA. Electronic address: cijiang.he@mssm.edu.
6
National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China. Electronic address: liuzhihong@nju.edu.cn.

Abstract

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.

KEYWORDS:

combination therapy; gene expression profiling; immunosuppressive therapy; kidney cells; lupus nephritis; mycophenolate mofetil; tacrolimus

PMID:
29102373
DOI:
10.1016/j.kint.2017.08.031
[Indexed for MEDLINE]

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