RG LANGHAM1,2, S MARTINI3, F EICHINGER3, V NAIR3, Y ZHANG1, A COX1, M KRETZLER3, D J KELLY1
1St. Vincent’s Hospital University of Melbourne Department of Medicine, Fitzroy, VIC; 2Monash University School of Rural Health, Clayton, VIC 3University of Michigan, Ann Arbour, MI, USA.
Background; Transcriptomic analysis of diabetic nephropathy (DN) biopsies has provided information into the molecular pathways that may drive disease. In this study, we aimed to measure the transcriptional changes of a new anti-fibrotic, FT011, in a rodent model of DN and to compare findings to that already described in human DN.
Method; Control and diabetic Ren(2) rats were treated with FT-011 (200mg/kg/day) or vehicle for 16 weeks (Early) or for the last 2 days of the 16-week period (Late). Total RNA was isolated from renal cortex, reverse transcribed, linearly amplified, and hybridized on Affymetrix microarrays. Identification of significantly differentially regulated genes between the cohorts for their enrichment in canonical pathways and functional groupings was done using the Ingenuity® Pathway Analysis Software Suite.
Results; Gene expression in DN showed early findings consistent with Type 1 diabetes. Early FT011-treatment of DN showed an acute up-regulation of Fatty acid oxidation pathways, while the longer term changes after 16-week treatment showed suppression of activated inflammatory pathways, suppression of drivers of fibrosis and of transcriptional regulators known to be involved in progressive forms of DN (STAT1). Reduced inhibitory effect on inflammatory pathways was seen with Late treatment. Comparison with the human DN data demonstrated several overlapping key features and pathways of the human DN to be recapitulated in the animal model.
Conclusion; Analysis of transcriptional changes mediated by FT011 has demonstrated a sustained anti-inflammatory and anti-fibrotic action. Similarity of the changes seen in the human transcriptional data set highlights the ability of FT011 to modulate key signaling pathways identified as important in the pathogenesis of human DN, and further supports its potential utility as a new therapy for DN.