Positioning of Tacrolimus for the Treatment of Diabetic Nephropathy Based on Computational Network Analysis

PLoS One. 2017 Jan 6;12(1):e0169518. doi: 10.1371/journal.pone.0169518. eCollection 2017.

Abstract

Objective: To evaluate tacrolimus as therapeutic option for diabetic nephropathy (DN) based on molecular profile and network-based molecular model comparisons.

Materials and methods: We generated molecular models representing pathophysiological mechanisms of DN and tacrolimus mechanism of action (MoA) based on literature derived data and transcriptomics datasets. Shared enriched molecular pathways were identified based on both model datasets. A newly generated transcriptomics dataset studying the effect of tacrolimus on mesangial cells in vitro was added to identify mechanisms in DN pathophysiology. We searched for features in interference between the DN molecular model and the tacrolimus MoA molecular model already holding annotation evidence as diagnostic or prognostic biomarker in the context of DN.

Results: Thirty nine molecular features were shared between the DN molecular model, holding 252 molecular features and the tacrolimus MoA molecular model, holding 209 molecular features, with six additional molecular features affected by tacrolimus in mesangial cells. Significantly affected molecular pathways by both molecular model sets included cytokine-cytokine receptor interactions, adherens junctions, TGF-beta signaling, MAPK signaling, and calcium signaling. Molecular features involved in inflammation and immune response contributing to DN progression were significantly downregulated by tacrolimus (e.g. the tumor necrosis factor alpha (TNF), interleukin 4, or interleukin 10). On the other hand, pro-fibrotic stimuli being detrimental to renal function were induced by tacrolimus like the transforming growth factor beta 1 (TGFB1), endothelin 1 (EDN1), or type IV collagen alpha 1 (COL4A1).

Conclusion: Patients with DN and elevated TNF levels might benefit from tacrolimus treatment regarding maintaining GFR and reducing inflammation. TGFB1 and EDN1 are proposed as monitoring markers to assess degree of renal damage. Next to this stratification approach, the use of drug combinations consisting of tacrolimus in addition to ACE inhibitors, angiotensin receptor blockers, TGFB1- or EDN1-receptor antagonists might warrant further studies.

MeSH terms

  • Biomarkers
  • Computational Biology / methods*
  • Diabetic Nephropathies / drug therapy
  • Diabetic Nephropathies / genetics*
  • Diabetic Nephropathies / metabolism*
  • Gene Expression Profiling
  • Humans
  • Immunosuppressive Agents / pharmacology*
  • Mesangial Cells / drug effects
  • Mesangial Cells / metabolism
  • Models, Biological*
  • Tacrolimus / pharmacology*
  • Transcriptome

Substances

  • Biomarkers
  • Immunosuppressive Agents
  • Tacrolimus

Grants and funding

Financial support was provided by an unrestricted grant from Chiesi. The funder did not have a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. AH and PP are employees of emergentec biodevelopment GmbH. emergentec biodevelopment GmbH provided support in the form of salaries for authors AH and PP, but did not have any additional role in the study design, decision to publish or preparation of the manuscript. The specific roles of these authors are articulated in the author contributions‘ section.