Journal
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
Volume 27, Issue 1, Pages 69-77Publisher
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2014090856
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Funding
- Kids Kidney Research
- Kidney Research UK [RP38/2013]
- Kidney Research UK Senior Non-Clinical Fellowship [SF1/2008]
- Medical Research Council New Investigator Award [MR/J003638/1]
- National Heart, Lung, and Blood Institute of US National Institutes of Health [P01-HL024136, R01-HL059157]
- ICH/GOSH Biomedical Research Centre
- Manchester Biomedical Research Centre
- Medical Research Council [MR/K026739/1, MR/L012707/1]
- MRC [MR/K026739/1, MR/L002744/1, MR/J003638/1] Funding Source: UKRI
- Kidney Research UK [SF1/2008] Funding Source: researchfish
- Medical Research Council [MR/J003638/1, MR/L002744/1] Funding Source: researchfish
- Great Ormond Street Hospital Childrens Charity [V1403] Funding Source: researchfish
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL059157, P01HL024136, R01HL127402] Funding Source: NIH RePORTER
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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 autosonnal 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.
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