PPARgamma Repression Of Tubular Epithelial Cell dysmetabolism to Treat Fibrosis – PROTECT-FI

The PROTECT-Fi project will be conducted in a non-investigated field regarding treatment innovation.

The study is based on our original observations:

1/ A key transcription factor, PPARG, that regulates metabolism in renal tubular epithelial cells (TECs) is lost, particularly in mice and patients with necrotizing crescentic rapidly progressive glomerulonephritis (RPGN) but also in a severe model of Collapsing Glomerulopathy (CoG), a disease with no treatment.

2/ When inflammation precedes fibrosis the lost constitutive expression of PPARg coincides with activation of the STAT3 and SMAD3 profibrotic cascades in the same kidney cells in both diseases.

3/ Strikingly, pharmacological PPARg agonism represses STAT3 and SMAD3 phosphorylation, inflammation, and fibrosis in two mechanistically unrelated animal models, of RPGN and of CoG.

We hypothesize this uncovers a novel connection between cell metabolism and sterile inflammation in renal TEC that will be investigated using the same functional and molecular imaging and analyses of patients' tissues and mouse models.

To progress in the exploration of this candidate approach which offers promising prospects for therapeutic repositioning, the PROTECT-Fi project is setting up a translational platform allowing the exceptional exploration of the relationships between cellular metabolism and chronic renal sterile inflammation thanks to a cross-species integrative approach supporting a new way of exploring the clinical and biological trajectories of patients suffering from these extremely severe glomerular renal diseases.