Huang, JL;
Woolf, AS;
Kolatsi-Joannou, M;
Baluk, P;
Sandford, RN;
Peters, DJM;
McDonald, DM;
... Long, DA; + view all
(2015)
Vascular endothelial growth factor C therapy for polycystic kidney diseases.
Journal of the American Society of Nephrology
, 27
(1)
pp. 69-77.
10.1681/ASN.2014090856.
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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 Pkd1nl/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 Pkd1nl/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 Pkd1nl/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 Cys1cpk/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.
| Type: | Article |
|---|---|
| Title: | Vascular endothelial growth factor C therapy for polycystic kidney diseases. |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1681/ASN.2014090856 |
| Publisher version: | http://dx.doi.org/ 10.1681/ASN.2014090856 |
| Language: | English |
| Additional information: | Copyright © 2015 by the American Society of Nephrology |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1463573 |
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