Meta-analysis of polycystic kidney disease expression profiles defines strong involvement of injury repair processes

Abstract

Polycystic kidney disease (PKD) is a major cause of end-stage renal disease. The disease mechanisms are not well understood and the pathogenesis toward renal failure remains elusive. In this study, we present the first RNASeq analysis of a -mutant mouse model in a combined meta-analysis with other published PKD expression profiles. We introduce the PKD Signature, a set of 1,515 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-κB signaling, epithelial-mesenchymal transition, inflammatory response, hypoxia, and metabolism were among 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-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.

Prioritization of novel ADPKD drug candidates from disease-stage specific gene expression profiles

“…Inflammation and associated fibrosis became even more prominent in the advanced phase with increased expression of macrophage markers [49,50]. Furthermore, in the late-phase we see evidence of severe cell damage and tissue injury response with the upregulation of pathways involved in oxidative stress, DNA damage response, and P53 signaling [29,51].…”

Periostin overexpression in collecting ducts accelerates renal cyst growth and fibrosis in polycystic kidney disease

“…Cystic epithelial cells are characterized as being incompletely differentiated with increased c-myc expression, persistent activation of mTOR, aberrant cell proliferation, and elevated secretion of growth factors, chemokines, and matrix components (5,11,47,56,58). Analysis of PKD-related gene expression revealed that genes involved in tissue repair pathways were highly enriched in the PKD gene profile (33). Cyst cells have a loss of expression of kidney epithelium-specific genes and upregulation of developmental and mitogenic pathways (56), as well as TGF-␤-Smad signaling, matrix production, Rho signaling, and cytoskeleton remodeling (7, 18).…”

“…Evidence has demonstrated a link between kidney injury and cyst initiation and PKD progression (2,4,17,33,44,69); however, it remains unclear whether factors involved in tissue repair contribute to cyst growth and fibrosis in polycystic kidney disease (PKD) kidneys. In this study, we determined that selective overexpression of periostin in collecting ducts (CD), a predominant site for cyst formation, was not sufficient to induce cyst initiation in otherwise normal mice.…”

Nanopublications: A Growing Resource of Provenance-Centric Scientific Linked Data

“…A small dataset on a meta-analysis of polycystic kidney disease expression profiles was derived from sequenced male mouse RNA data [24]. The data is split into three phases of disease progression: early, moderate, and advanced.…”