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Dysregulated mesenchymal PDGFR-β drives kidney fibrosis

ABSTRACT: Kidney fibrosis is characterized by expansion and activation of platelet-derived growth factor receptor-β (PDGFR-β) positive mesenchymal cells. To study the consequences of PDGFR-ß activation, we developed a model of primary renal fibrosis using transgenic mice with PDGFR-β activation specifically in renal mesenchymal cells, driving their pathological proliferation and phenotypic switch towards myofibroblasts. This resulted in progressive mesangioproliferative glomerulonephritis, mesangial sclerosis and interstitial fibrosis with progressive anemia due to loss of erythropoietin production by fibroblasts. We used microarrays to compare wildtype animals (Foxd1_wt Pdgfrb_wt) to animals with constitutive mesenchymal PDGFR-β activation (Foxd1_mt Pdgfrb V536A) in the kidney to identify target genes of PDGFR-β signaling. Overall design: To generate mice with a renal mesenchymal cell-specific, constitutively active PDGFR-β (Foxd1_mt Pdgfrb V536A), we used mice in which one wt Pdgfrb allele was substituted by a conditional knock-in of Pdgfrb with an activating point mutation (V536A) in the juxtamembrane domain of PDGFR-β, behind a floxed STOP cassette. Expression of the mutated Receptor occurs after Cre-recombinase excision. Cre-recombinase expression occurs under the FoxD1-promoter, which is active in renal mesenchymal precursors during development. Foxd1_mt Pdgfrb V536A mice were compared to wildtype littermates Foxd1_wt Pdgfrb_wt.

INSTRUMENT(S): [MTA-1_0] Affymetrix Mouse Transcriptome Array 1.0 [transcript (gene) CSV version]

ORGANISM(S): Mus musculus

SUBMITTER: Bernd Denecke

PROVIDER: GSE138819 | GEO | 2019-12-06

REPOSITORIES: GEO

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