title: Genetic inactivation of prokineticin receptor-1 leads to heart and kidney disorders.
abstract: OBJECTIVE
  Prokineticins are potent angiogenic hormones that use 2 receptors, prokineticin receptor-1 (PKR1) and PKR2, with important therapeutic use in anticancer therapy. Observations of cardiac and renal toxicity in cancer patients treated with antiangiogenic compounds led us to explore how PKR1 signaling functioned in heart and kidney in vivo.
  
  
  RESULTS
  We generated mice with a conditional disruption of the PKR1 gene. We observed that PKR1 loss led to cardiomegaly, severe interstitial fibrosis, and cardiac dysfunction under stress conditions, accompanied by renal tubular dilation, reduced glomerular capillaries, urinary phosphate excretion, and proteinuria at later ages. Abnormal mitochondria and increased apoptosis were evident in both organs. Perturbation of capillary angiogenesis in both organs was restored at the adult stage potentially via upregulation of hypoxia-inducible factor-1 and proangiogenic factors. Compensatory mechanism could not revoke the epicardial and glomerular capillary networks, because of increased apoptosis and reduced progenitor cell numbers, consistent with an endogenous role of PKR1 signaling in stimulating epicardin+ progenitor cell proliferation and differentiation.
  
  
  CONCLUSIONS
  Here, we showed for the first time that the loss of PKR1 causes renal and cardiac structural and functional changes because of deficits in survival signaling, mitochondrial, and progenitor cell functions in found both organs.
authors.affiliation: Centre National de la Recherche Scientifique, Université de Strasbourg, UMR 7242, Ecole Supérieure de Biotechnologie de Strasbourg, Illkirch, France.
authors.forename: Mounia
authors.initials: M
authors.lastname: Boulberdaa
authors.forename: Gulen
authors.initials: G
authors.lastname: Turkeri
authors.forename: Kyoji
authors.initials: K
authors.lastname: Urayama
authors.forename: Mojdeh
authors.initials: M
authors.lastname: Dormishian
authors.forename: Cécilia
authors.initials: C
authors.lastname: Szatkowski
authors.forename: Luc
authors.initials: L
authors.lastname: Zimmer
authors.forename: Nadia
authors.initials: N
authors.lastname: Messaddeq
authors.forename: Virginie
authors.initials: V
authors.lastname: Laugel
authors.forename: Pascal
authors.initials: P
authors.lastname: Dollé
authors.forename: Canan G
authors.initials: CG
authors.lastname: Nebigil
mesh_terms: D000375:Aging; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D006331:Heart Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic; D010641:Phenotype; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D016277:Ventricular Function, Left
chemical_list: C525015:PKR1 protein, mouse; D043562:Receptors, G-Protein-Coupled