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. METHODS AND 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.
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 cancerpatients treated with antiangiogenic compounds led us to explore how PKR1 signaling functioned in heart and kidney in vivo. METHODS AND 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: Glen S Patten; Caroline A Kerr; Robert A Dunne; Janet M Shaw; Anthony R Bird; Ahmed Regina; Matthew K Morell; Trevor J Lockett; Peter L Molloy; Mahinda Y Abeywardena; David L Topping; Michael A Conlon Journal: Dig Dis Sci Date: 2015-01-24 Impact factor: 3.199
Authors: Reka Nagy; Thibaud S Boutin; Jonathan Marten; Jennifer E Huffman; Shona M Kerr; Archie Campbell; Louise Evenden; Jude Gibson; Carmen Amador; David M Howard; Pau Navarro; Andrew Morris; Ian J Deary; Lynne J Hocking; Sandosh Padmanabhan; Blair H Smith; Peter Joshi; James F Wilson; Nicholas D Hastie; Alan F Wright; Andrew M McIntosh; David J Porteous; Chris S Haley; Veronique Vitart; Caroline Hayward Journal: Genome Med Date: 2017-03-07 Impact factor: 11.117