Human PKD2 blocking peptide

Introduction: Polycystic kidney disease (PKD) is clinically and genetically heterogeneous and constitutes the most common heritable kidney disease. Most patients are affected by the autosomal dominant form (ADPKD) which generally is an adult-onset multisystem disorder. By contrast, the rarer recessive form ARPKD usually already manifests perinatally or in childhood. In some patients, however, ADPKD and ARPKD can phenotypically overlap with early manifestation in ADPKD and only late onset in ARPKD. Progressive fibrocystic renal changes are often accompanied by severe hepatobiliary changes or other extrarenal abnormalities. Areas covered: A reduced dosage of disease proteins disturbs cell homeostasis and explains a more severe clinical course in some PKD patients. Cystic kidney disease is also a common feature of other ciliopathies and genetic syndromes. Genetic diagnosis may guide clinical management and helps to avoid invasive measures and to detect renal and extrarenal comorbidities early in the clinical course. Expert Commentary: The broad phenotypic and genetic heterogeneity of cystic and polycystic kidney diseases make NGS a particularly powerful approach. Interpretation of data becomes the challenge and bench and bedside benefit from digitized multidisciplinary interrelationships.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, caused in the majority of the cases by a mutation in either the PKD1 or the PKD2 gene. ADPKD is characterised by a progressive increase in the number and size of cysts, together with fibrosis and distortion of the renal architecture, over the years. This is accompanied by alterations in a complex network of signalling pathways. However, the underlying molecular mechanisms are not well characterised. Previously, we defined the PKD Signature, a set of genes typically dysregulated in PKD across different disease models from a meta-analysis of expression profiles. Given the importance of transcription factors (TFs) in modulating disease, we focused in this paper on characterising TFs from the PKD Signature. Our results revealed that out of the 1515 genes in the PKD Signature, 92 were TFs with altered expression in PKD, and 32 of those were also implicated in tissue injury/repair mechanisms. Validating the dysregulation of these TFs by qPCR in independent PKD and injury models largely confirmed these findings. STAT3 and RUNX1 displayed the strongest activation in cystic kidneys, as demonstrated by chromatin immunoprecipitation (ChIP) followed by qPCR. Using immunohistochemistry, we showed a dramatic increase of expression after renal injury in mice and cystic renal tissue of mice and humans. Our results suggest a role for STAT3 and RUNX1 and their downstream targets in the aetiology of ADPKD and indicate that the meta-analysis approach is a viable strategy for new target discovery in PKD.