Abstract
BackgroundAlthough 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.ResultsWe 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.ConclusionsOur 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.
Highlights
Renal fibrosis and inflammation have shown to be involved in the pathophysiology of obstructive nephropathies, molecular mechanisms underlying evolution of these processes remain undetermined
Identification of most prominent dysregulated miRNAs commonly associated with obstructive nephropathy in humans and mice To prioritize the molecular features with potentially the highest impact on the development of kidney lesions, we identified the miRNAs that could consistently reflect the human disease by comparing the similarity of the human and animal miRNA signature taking advantage from the fact that miRNAs are well conserved between species [26]
To what we observed in partial ureteral obstruction (UUO) in neonatal mice, Dtx4 and navigator 1 (Nav1) expression was significantly increased in UUO mice compared to the sham (Fig. 3a and c), while Lmod1 was not modified (Fig. 3b)
Summary
Renal fibrosis and inflammation have shown to be involved in the pathophysiology of obstructive nephropathies, molecular mechanisms underlying evolution of these processes remain undetermined. Congenital obstructive nephropathy is the main cause of end stage renal disease (ESRD) in children [1]. The gold standard in diagnosis of UPJ is by prenatal ultrasonography with subsequent evaluation in the postnatal period [5] This method is not sensitive enough to accurately estimate renal function and functioning nephron number [6]. This has led to an urgent need for the development of biomarkers to assess the severity of UPJ obstruction and to help the clinicians to decide if and when pyeloplasty is required [5, 7]
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