Signaling Modulators that Support Progression in Diabetic Nephropathy audioicon

An expanding literature describes the contribution of TGF-beta signaling to multiple facets of DN progression and the potential of BMP-7 to restrict this progression, at least in part by opposing TGF-beta signaling. However, confounding the effectiveness of BMP-7 is the fact that DN progression sees an increase in the production of soluble extracellular BMP antagonists. For instance, we have reported the increased expression of the BMP antagonist, gremlin, in cell culture and animal models of DN and during progression of human DN.

In addition, we have shown that mono-allelic deletion of the gremlin gene protects from kidney damage in a model of type I diabetes in the mouse. Interestingly, interrogation of the gremlin promoter identified a cluster of transcription factor binding elements that were shared with other reported pro-nephropathic modulators, among them, CTGF and the notch ligand, jagged1. We will now describe in silico molecular modeling analyses coupled with cell culture based testing protocols which seek to identify modified BMP ligands that are resistant to antagonist binding [‘super-agonists’], modified ligands that no longer bind receptor but still bind antagonist [‘dominant negatives’] and functionally defective modified antagonist molecules that fail to bind BMP-7 but still dimerize [‘antagonist sinks’]. This strategy will hopefully identify new biologic leads of therapeutic interest. In parallel, we are characterizing a novel mitochondrial protein, IHG-1, that amplifies TGF-beta signaling, at least in part by modulating smad7 expression and a modified IHG-1 that ablates TGF-beta actions. These studies are coupled with expression analyses that seek to comprehensively describe the TGF-beta triggered ‘transcriptome’ that supports progression in DN: We are integrating RNA-seq expression data from cell culture models and human kidney biopsies with microarray expression profiles from animal models of DN to achieve this aim.

Authors: S. Surae, E. Brennan, D. Walsh, M. Morine, S. Roxburgh, F. Hickey, D. Brazil, D. Higgins, J. Crean, M. Murphy, C. Godson and F. Martin.
Diabetes Research Center, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.

Supported by Science Foundation Ireland. Included are activities of The Genie Consortium, the authors are grateful to the other members of the consortium for their input.

This was presented at the ISN Forefronts Symposium event “Systems Biology and the Kidney” that took place from 7-10 June 2012 in AnnArbor , Michigan, US.

 

Additional Info

  • Contains Audio:
    Yes
  • Source:
    ISN
  • Event:
    Forefronts
  • Year:
    2012
  • Members Only:
    No



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Last modified on Saturday, 22 March 2014 20:20

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