Identificazione di pattern di espressione genica della displasia renale associata ad uropatia malformativa

Normal kidney and urinary tract development is a complex process, regulated by a strict space-time-corrected sequential activation of a cascade of genes encoding transcription factors, growth factors, cell death/proliferation factors and adhesion molecules. An alteration disrupting this sequential gene expression may cause a defective ureteric bud-to-metanephric mesenchyme cross-talk that results in a renal and urinary tract developmental abnormality (congenital anomalies of kidney and urinary tract - CAKUT). Phenotype severity depends on the stage of nephrogenesis in which the alteration of the developmental program occurs, thus renal dysplasia is the most severe manifestation. However, little is known about CAKUT pathogenesis. The recent advent of microarray technology provided an unique tool to identify genes potentially involved in the pathogenesis of several diseases. During the first stage of this research, we applied the microarray technique to study gene expression profiles of primary renal cell cultures, using an array composed by 21329 oligonucleotides. The aim was to identify potential biomarkers of renal dysplasia. Four genes seemed to be more interesting (UPK1B, SOX11, SPRY1, MMP2). We analysed the expression of these four genes using Real Time PCR on RNA extracted from renal tissue samples of 10 patients with a histological picture of renal dysplasia and 10 with histologically normal renal tissue. Mutation analysis of SPRY1 gene, whose murine homologue is hugely involved in the regulation of GDNF growth factor's expression during ureteric branching, was carried out on 27 patients with renal duplicity. Mutation analysis identified 2 new genomic variants - whose frequency was analysed in a control population - that may be "genomic variants involved in splicing" (SpaGVs). Our research results allow to hypothesize that SPRY1 gene may be involved in the pathogenesis of kidney and urinary tract developmental diseases.