title: Six2creFrs2α knockout mice are a novel model of renal cystogenesis.
abstract: Six2cre-mediated deletion of Frs2α (Six2creFrs2αKO), a major fibroblast growth factor receptor (Fgfr) docking protein in mouse nephron progenitors results in perinatal renal hypoplasia; however, postnatal Six2creFrs2αKO kidneys develop cysts. We sought to determine the pathogenesis of Six2creFrs2αKO cyst formation. We performed histological assays, Western blots, and quantitative PCR (qPCR). While embryonic day (E) 18.5 Six2Frs2αKO kidneys were hypoplastic and not cystic, postnatal day (P) 7 mutants had proximal tubular-derived cysts that nearly replaced the renal parenchyma by P21. Mutants had high proximal tubular proliferation rates and interstitial fibrosis, similar to known polycystic kidney disease (PKD) models. Six2creFrs2αKO kidneys also had upregulation of Wnt/βcatenin signaling, macrophage infiltration and chemokine production (e.g. ectopic Ccl2 in non-dilated proximal tubules), and augmented hedgehog signaling, features also seen in other PKD models. We saw increased Gli1 (hedgehog readout) in postnatal Six2creFrs2αKO interstitium and ectopic sonic hedgehog (Shh) in subsets of non-dilated P7 mutant proximal tubules (likely driving the stromal Gli expression). As ectopic tubular Shh and Ccl2 expression is seen after acute kidney injury (AKI), we interrogated another bone fide AKI marker, Kim1 and noted ectopic expression in P7 non-dilated proximal tubules. These observations suggest that aberrantly activated "AKI" pathways may drive pathogenesis in PKD.
authors.affiliation: Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Pawan
authors.initials: P
authors.lastname: Puri
authors.affiliation: Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bushnell
authors.affiliation: Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Caitlin M
authors.initials: CM
authors.lastname: Schaefer
authors.affiliation: Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.
authors.forename: Carlton M
authors.initials: CM
authors.lastname: Bates
mesh_terms: D000818:Animals; D017209:Apoptosis; D001806:Blood Urea Nitrogen; D049109:Cell Proliferation; D018925:Chemokines / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism; D005786:Gene Expression Regulation; D053823:Hedgehog Proteins / Q000378:metabolism; D000072596:Hepatitis A Virus Cellular Receptor 1 / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D007249:Inflammation; D007668:Kidney / Q000196:embryology* / Q000254:growth & development / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D007690:Polycystic Kidney Diseases / Q000235:genetics* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1 / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D018925:Chemokines; C488187:FRS2alpha protein, mouse; C498520:Gli1 protein, mouse; C442240:Havcr1 protein, mouse; D053823:Hedgehog Proteins; D000072596:Hepatitis A Virus Cellular Receptor 1; D018398:Homeodomain Proteins; D008565:Membrane Proteins; C465570:Shh protein, mouse; C497420:Six2 protein, mouse; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D051176:beta Catenin