Polycystic Kidney Disease is a major cause of end-stage renal disease. The disease mechanisms are not well understood and the pathogenesis towards renal failure remains elusive. In this study, we present the first RNASeq analysis of a Pkd1-mutant mouse model in a combined meta-analysis with other published PKD expression profiles. We introduce the PKD signature, a set of 1515 genes that are commonly dysregulated in PKD studies. We show that the signature genes include many known and novel PKD-related genes and functions. Moreover, genes with a role in injury repair, as evidenced by expression data and/or automated literature analysis, were significantly enriched in the PKD signature, with 35% of the PKD signature genes being directly implicated in injury repair. NF-B signaling, epithelial-mesenchymal transition, inflammatory response, hypoxia, and metabolism were amongst the most prominent injury or repair-related biological processes with a role in the PKD etiology. Novel PKD genes with a role in PKD and in injury were confirmed in another Pkd1-mutant mouse model as well as in animals treated with a nephrotoxic agent. We propose that compounds that can modulate the injury-repair response, could be valuable drug candidates for PKD treatment.