Network analysis of a Pkd1-mouse model of autosomal dominant polycystic kidney disease identifies HNF4α as a disease modifier

PLoS Genet. 2012;8(11):e1003053. doi: 10.1371/journal.pgen.1003053. Epub 2012 Nov 29.

Abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD; MIM ID's 173900, 601313, 613095) leads to end-stage kidney disease, caused by mutations in PKD1 or PKD2. Inactivation of Pkd1 before or after P13 in mice results in distinct early- or late-onset disease. Using a mouse model of ADPKD carrying floxed Pkd1 alleles and an inducible Cre recombinase, we intensively analyzed the relationship between renal maturation and cyst formation by applying transcriptomics and metabolomics to follow disease progression in a large number of animals induced before P10. Weighted gene co-expression network analysis suggests that Pkd1-cystogenesis does not cause developmental arrest and occurs in the context of gene networks similar to those that regulate/maintain normal kidney morphology/function. Knowledge-based Ingenuity Pathway Analysis (IPA) software identifies HNF4α as a likely network node. These results are further supported by a meta-analysis of 1,114 published gene expression arrays in Pkd1 wild-type tissues. These analyses also predict that metabolic pathways are key elements in postnatal kidney maturation and early steps of cyst formation. Consistent with these findings, urinary metabolomic studies show that Pkd1 cystic mutants have a distinct profile of excreted metabolites, with pathway analysis suggesting altered activity in several metabolic pathways. To evaluate their role in disease, metabolic networks were perturbed by inactivating Hnf4α and Pkd1. The Pkd1/Hnf4α double mutants have significantly more cystic kidneys, thus indicating that metabolic pathways could play a role in Pkd1-cystogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Animals
  • Cell Proliferation
  • Disease Models, Animal
  • Gene Expression Regulation
  • Gene Regulatory Networks*
  • Hepatocyte Nuclear Factor 4* / genetics
  • Hepatocyte Nuclear Factor 4* / metabolism
  • Humans
  • Mice
  • Mutation
  • Polycystic Kidney, Autosomal Dominant* / genetics
  • Polycystic Kidney, Autosomal Dominant* / metabolism
  • Protein Kinase C* / genetics
  • Protein Kinase C* / metabolism

Substances

  • HNF4B protein, human
  • Hepatocyte Nuclear Factor 4
  • protein kinase D
  • Protein Kinase C

Associated data

  • GEO/GSE24532