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.

Vascular Endothelial Growth Factor Therapy for the Kidney

“…Although PKD-induced neovascularization results in a disorganized and dysfunctional vascular network, previous studies showing antiangiogenic interventions in PKD by inhibition of VEGF did not result in improvements and may even accelerate the progression of the disease and renal deterioration. Therefore, the work by Huang et al 24 supports the notions that an intact VEGF-C pathway is pivotal in the pathophysiology of PKD and that the restarting of the VEGF-C/VEGFR3 pathway by VEGF-C therapy likely slowed the progression of renal injury and prolonged the survival of the treated animals.…”

“…The current therapeutic strategies focus on the management of chronic pain and hypertension as well as the unequivocal signs of renal compromise, which eventually develops and may lead to progressive renal failure and ESRD in adulthood in up to 60% of patients. 23 In this issue of JASN, Huang et al 24 provide supportive data for the development of a potential strategy for treating PKD using VEGF-C therapy. The growth of the pathognomonic cysts in PKD carries an expansion of the vasculature to supply newly developed structures, which are driven by enhanced renal angiogenic activity likely triggered by local hypoxia.…”

“…The growth of the pathognomonic cysts in PKD carries an expansion of the vasculature to supply newly developed structures, which are driven by enhanced renal angiogenic activity likely triggered by local hypoxia. The work by Huang et al 24 focuses on VEGF-C using mouse models of autosomal dominant Pkd1 nl/nl and a recessive form of PKD (Cys1 cpk/cpk ). Even in the absence of a sustained reduction in VEGF-C activity (only observed very early), administration of exogenous VEGF-C stimulates the downstream signaling of this cytokine, with a functional and structural consequence on the effect of PKD, because less damage and improvement in some markers of renal function were observed.…”

“…24 Although these models rapidly develop PKD, this study is most relevant to using VEGF-C as an intervention during very early stages of PKD in humans. 24 Thus, longer observation and/or administration of VEGF-C therapy at later stages of PKD (with greater development of renal damage) will be necessary to determine the true potential of this intervention.…”

“…24 Although these models rapidly develop PKD, this study is most relevant to using VEGF-C as an intervention during very early stages of PKD in humans. 24 Thus, longer observation and/or administration of VEGF-C therapy at later stages of PKD (with greater development of renal damage) will be necessary to determine the true potential of this intervention. Another potential limitation is that Huang et al 24 did not study markers of podocyte injury, which are a critical component of the glomerular filtration barrier and a major target of the VEGF-C/ VEGFR3 pathway, 26,27 or measure proteinuria in their study.…”