title: Vascular Endothelial Growth Factor C for Polycystic Kidney Diseases.
abstract: Polycystic kidney diseases (PKD) are genetic disorders characterized by progressive epithelial cyst growth leading to destruction of normally functioning renal tissue. Current therapies have focused on the cyst epithelium, and little is known about how the blood and lymphatic microvasculature modulates cystogenesis. Hypomorphic Pkd1(nl/nl) mice were examined, showing that cystogenesis was associated with a disorganized pericystic network of vessels expressing platelet/endothelial cell adhesion molecule 1 and vascular endothelial growth factor receptor 3 (VEGFR3). The major ligand for VEGFR3 is VEGFC, and there were lower levels of Vegfc mRNA within the kidneys during the early stages of cystogenesis in 7-day-old Pkd1(nl/nl) mice. Seven-day-old mice were treated with exogenous VEGFC for 2 weeks on the premise that this would remodel both the VEGFR3(+) pericystic vascular network and larger renal lymphatics that may also affect the severity of PKD. Treatment with VEGFC enhanced VEGFR3 phosphorylation in the kidney, normalized the pattern of the pericystic network of vessels, and widened the large lymphatics in Pkd1(nl/nl) mice. These effects were associated with significant reductions in cystic disease, BUN and serum creatinine levels. Furthermore, VEGFC administration reduced M2 macrophage pericystic infiltrate, which has been implicated in the progression of PKD. VEGFC administration also improved cystic disease in Cys1(cpk/cpk) mice, a model of autosomal recessive PKD, leading to a modest but significant increase in lifespan. Overall, this study highlights VEGFC as a potential new treatment for some aspects of PKD, with the possibility for synergy with current epithelially targeted approaches.
authors.affiliation: Developmental Biology and Cancer Programme, UCL Institute of Child Health, London, United Kingdom;
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Huang
authors.affiliation: Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, United Kingdom;
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Woolf
authors.affiliation: Developmental Biology and Cancer Programme, UCL Institute of Child Health, London, United Kingdom;
authors.forename: Maria
authors.initials: M
authors.lastname: Kolatsi-Joannou
authors.affiliation: Cardiovascular Research Institute, Comprehensive Cancer Center, and Department of Anatomy, University of California, San Francisco, California;
authors.forename: Peter
authors.initials: P
authors.lastname: Baluk
authors.affiliation: Academic Department of Medical Genetics, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom; and.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Sandford
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Dorien J M
authors.initials: DJ
authors.lastname: Peters
authors.affiliation: Cardiovascular Research Institute, Comprehensive Cancer Center, and Department of Anatomy, University of California, San Francisco, California;
authors.forename: Donald M
authors.initials: DM
authors.lastname: McDonald
authors.affiliation: Developmental Biology and Cancer Programme, UCL Institute of Child Health, London, United Kingdom;
authors.forename: Karen L
authors.initials: KL
authors.lastname: Price
authors.affiliation: Developmental Biology and Cancer Programme, UCL Institute of Child Health, London, United Kingdom;
authors.forename: Paul J D
authors.initials: PJ
authors.lastname: Winyard
authors.affiliation: Developmental Biology and Cancer Programme, UCL Institute of Child Health, London, United Kingdom; d.long@ucl.ac.uk.
authors.forename: David A
authors.initials: DA
authors.lastname: Long
mesh_terms: D000818:Animals; D051379:Mice; D007690:Polycystic Kidney Diseases / Q000188:drug therapy* / Q000209:etiology; D042582:Vascular Endothelial Growth Factor C / Q000502:physiology / Q000627:therapeutic use*
chemical_list: D042582:Vascular Endothelial Growth Factor C
keywords: endothelium; polycystic kidney disease; vascular endothelial growth factor