title: Acute kidney injury induces hallmarks of polycystic kidney disease.
abstract: Acute kidney injury (AKI) and autosomal dominant polycystic kidney disease (ADPKD) are considered separate entities that both frequently cause renal failure. Since ADPKD appears to depend on a polycystin-1 (Pc1) or Pc2 dosage mechanism, we investigated whether slow progression of cystogenesis in two Pkd1 transgenic mouse models can be accelerated with moderate ischemia-reperfusion injury (IRI). Transient unilateral left ischemic kidneys in both nontransgenic and transgenic mice reproducibly develop tubular dilatations, cysts, and typical PKD cellular defects within 3 mo post-IRI. Similar onset and severity of IRI induced-cystogenesis independently of genotype revealed that IRI is sufficient to promote renal cyst formation; however, this response was not further amplified by the transgene in Pkd1 mouse models. The IRI nontransgenic and transgenic kidneys showed from 16 days post-IRI strikingly increased and sustained Pkd1/Pc1 (>3-fold) and Pc2 (>8-fold) expression that can individually be cystogenic in mice. In parallel, long-term and important stimulation of hypoxia-inducible factor 1α expression was induced as in polycystic kidney disease. While mammalian target of rapamycin signaling is activated, stimulation of the Wnt pathway, with markedly increased active β-catenin and c-Myc expression in IRI renal epithelium, uncovered a similar regulatory cystogenic response shared by IRI and ADPKD. Our study demonstrates that long-term AKI induces cystogenesis and cross talk with ADPKD Pc1/Pc2 pathogenic signaling.
authors.affiliation: Molecular Genetics and Development, Institut de Recherches Cliniques de Montréal, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Almira
authors.initials: A
authors.lastname: Kurbegovic
authors.affiliation: Molecular Genetics and Development, Institut de Recherches Cliniques de Montréal, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada trudelm@ircm.qc.ca.
authors.forename: Marie
authors.initials: M
authors.lastname: Trudel
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D004195:Disease Models, Animal; D007511:Ischemia / Q000378:metabolism / Q000473:pathology*; D007668:Kidney / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D007690:Polycystic Kidney Diseases / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D050396:TRPP Cation Channels
keywords: Wnt cascade; acute kidney injury; ischemia/IRI; mTOR signaling; polycystin-1 and -2