Abstract: SA-PO322

Modulation of Upregulated Transcriptional Signaling Pathways in Rodent Diabetic Nephropathy after Treatment with a Novel Anti-Fibrotic Agent FT011: Correlates with Human Diabetic Kidney Disease

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Langham, Robyn G., Monash University, Melbourne, Victoria, Australia
  • Martini, Sebastian, Ludwig Maximilian University Munich, Munich, Germany
  • Eichinger, Felix H., University of Michigan , Ann Arbor, Michigan, United States
  • Nair, Viji, University of Michigan , Ann Arbor, Michigan, United States
  • Kretzler, Matthias, University of Michigan , Ann Arbor, Michigan, United States
  • Kelly, Darren J., St. Vincent's Hospital, Fitzroy, New South Wales, Australia
Background

Transcriptomic analysis of diabetic nephropathy (DN) biopsy tissue has provided valuable insights into the regulatory networks that may drive progressive disease. In this study, we undertook a transcriptomic analysis associated with demonstrated improved histological and clinical effects of a new anti-fibrotic, FT011, in a rodent model of DN. We also aimed to compare the animal findings with that already understood to be involved in human DN, a means of predicting utility of FT011 in humans.

Methods

Control and diabetic Ren(2) rats were treated with either FT-011(200mg/kg/day) or vehicle for 16 weeks(Early), or for the last 2 days of the study(Late). Total RNA was isolated from renal cortex, reverse transcribed, linearly amplified, and hybridized on Affymetrix microarrays. The Ingenuity® Pathway Analysis Software Suite was used for gene analysis.

Results

Gene expression data in diabetic rats showed early findings in keeping with Type 1 diabetes, early suppression of lymphocyte genes, and an increase in known diabetes-related genes. Short term FT011-treatment of rats with established DN showed acute up-regulation of Fatty acid oxidation pathways, while the longer term treatment showed a suppression of activated inflammatory pathways, and suppression of drivers of fibrosis (TGFß) and of transcriptional regulators known to be involved in progressive forms of DN (STAT1). Short-term late treatment with FT011 showed a reduced inhibitory effect on inflammatory pathways. Comparison with the transcriptome from human DN demonstrated several overlapping key features and pathways of the human disease to be recapitulated in the animal model used, with a significant z-score of 6.4.

Conclusion

Analysis of transcriptional changes mediated by treatment with FT011 has shown an early up-regulation of fatty acid oxidation, and a later, more sustained anti-inflammatory and anti-fibrotic action. Similarity of the changes seen in the animal model to the human transcriptional data set highlights the close alignment of this model to the human disease. As well, the ability of FT011 to modulate key signaling pathways identified as important in the pathogenesis of human DN further supports its potential utility as a new therapy for DN.