Systems biology combining human- and animal-data miRNA and mRNA data identifies new targets in ureteropelvic junction obstruction

Theofilos Papadopoulos, Audrey Casemayou, Eric Neau, Benjamin Breuil, Cécile Caubet, Denis Calise, Barbara A. Thornhill, Magdalena Bachvarova, Julie Belliere, Robert L. Chevalier, Panagiotis Moulos, Dimcho Bachvarov, Benedicte Buffin-Meyer, Stéphane Decramer, Françoise Conte Auriol, Jean-Loup Bascands, Joost P. Schanstra, Julie Klein

Although renal fibrosis and inflammation have shown to be involved in the pathophysiology of obstructive nephropathies, molecular mechanisms underlying evolution of these processes remain undetermined. In an attempt towards improved understanding of obstructive nephropathy and improved translatability of the results to clinical practice we have developed a systems biology approach combining omics data of both human and mouse obstructive nephropathy. We have studied in parallel the urinary miRNome of infants with ureteropelvic junction obstruction and the kidney tissue miRNome and transcriptome of the corresponding neonatal partial unilateral ureteral obstruction (UUO) mouse model. Several hundreds of miRNAs and mRNAs displayed changed abundance during disease. Combination of miRNAs in both species and associated mRNAs let to the prioritization of five miRNAs and 35 mRNAs associated to disease. In vitro and in vivo validation identified consistent dysregulation of let-7a-5p and miR-29-3p and new potential targets, E3 ubiquitin-protein ligase (DTX4) and neuron navigator 1 (NAV1), potentially involved in fibrotic processes, in obstructive nephropathy in both human and mice that would not be identified otherwise. Our study is the first to correlate a mouse model of neonatal partial UUO with human UPJ obstruction in a comprehensive systems biology analysis. Our data revealed let-7a and miR-29b as molecules potentially involved in the development of fibrosis in UPJ obstruction via the control of DTX4 in both man and mice that would not be identified otherwise.