Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases

Eremina, Vera; Sood, Manish M.; Haigh, Jody J.; Nagy, András; Lajoie, Ginette; Ferrara, Napoleone; Gerber, Hans Peter; Kikkawa, Yamato; Miner, Jeffrey H.; Quaggin, Susan E.

doi:10.1172/jci17423

Cited by 1,109 publications

(680 citation statements)

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“…20 Also rats or mice injected with a sFlt-1 or overexpressing sFlt-1 by virus injection develop endotheliosis and proteinuria. 7,21,22 Collectively, these findings indicate that interference with the VEGF-A signaling pathway, either genetically or by a soluble receptor trapping VEGF, or by a tyrosine kinase directly targeting VEGF receptors, results in a similar glomerular phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…23 VEGF produced by podocytes is essential for the maintenance of the integrity of glomerular endothelial cells. 20,24 In addition, VEGF is also required for the maintenance of podocyte function and slit-diaphragm proteins, implying that podocyte-derived VEGF exerts both paracrine and autocrine effects. 25 In preeclamptic patients and mice exposed to a VEGF antibody or sFlt-1, nephrin expression decreases.…”

Section: Discussionmentioning

confidence: 99%

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Greater Sensitivity of Blood Pressure Than Renal Toxicity to Tyrosine Kinase Receptor Inhibition With Sunitinib

et al. 2015

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Abstract-Hypertension and renal injury are off-target effects of sunitinib, a tyrosine kinase receptor inhibitor used for the treatment of various tumor types. Importantly, these untoward effects are accompanied by activation of the endothelin system. Here, we set up a study to explore the dose dependency of these side effects. Normotensive Wistar Kyoto rats were exposed to 3 different doses of sunitinib or vehicle. After 8 days, rats were euthanized. Telemetrically measured blood pressure rose dose dependently, from 13 to 30 mm Hg. Proteinuria was present at all doses, but a rise in cystatin C occurred only at the intermediate and high doses. Compared with vehicle circulating endothelin-1 increased dose dependently, whereas 24-hour urinary endothelin excretion decreased. Light and electron microscopy revealed glomerular endotheliosis and ischemia with the intermediate and high doses of sunitinib but completely absent histological abnormalities with the low dose. Podocyte number per glomerular circumference did not change. Glomerular nephrin, Neph1, podocin, and endothelin-converting enzyme gene expression were downregulated in a dose-dependent manner.We conclude that the sunitinib-induced rise in blood pressure requires lower doses than its induction of renal function impairment and that functional changes in glomerular filtration barrier contribute to the occurrence of proteinuria, given the lack of histopathologic changes with the low dose of sunitinib. (Hypertension. 2015;66:543-549.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Greater Sensitivity of Blood Pressure Than Renal Toxicity to Tyrosine Kinase Receptor Inhibition With Sunitinib

et al. 2015

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“…51 Mice lacking VEGF demonstrate abnormal glomerular pathology, with loss of podocytes and disruption of the basement membrane. 52,53 This, together with thrombotic microangiopathy in the glomeruli, correlates clinically with proteinuria observed in patients treated with VEGF inhibitors. 52,54 VEGF-targeted therapies are associated with a 3-fold increase in risk for arterial thromboembolic events (stroke, transient ischemic attacks, myocardial infarction, angina, and other arterial events).…”

Section: Trastuzumab and Her2-targeted Agentsmentioning

confidence: 91%

Cardio-Oncology

Lenneman

Sawyer

2016

Circulation Research

348

138

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Through the success of basic and disease-specific research, cancer survivors are one of the largest growing subsets of individuals accessing the healthcare system. Interestingly, cardiovascular disease is the second leading cause of morbidity and mortality in cancer survivors after recurrent malignancy. This recognition has helped stimulate a collaboration between oncology and cardiology practitioners and researchers, and the portmanteau cardio-oncology (also known as onco-cardiology) can now be found in many medical centers. This collaboration promises new insights into how cancer therapies impact cardiovascular homeostasis and long-term effects on cancer survivors. In this review, we will discuss the most recent views on the cardiotoxicity related to various classes of chemotherapy agents and radiation. We will also discuss broadly the current strategies for treating and preventing cardiovascular effects of cancer therapy.

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“…23,27,28 Reduction of VEGF expression by 50% in the glomeruli using genetically modified mice leads to proteinuria and glomerular endothelial damage that resemble preeclampsia. 29 Furthermore, VEGF antagonists, used in patients with cancer, sometimes produce a preeclampsia-like phenotype including hypertension, glomerular endothelial damage, and reversible posterior leucoencephalopathy that is often noted in eclampsia. [30][31][32][33] These data support the hypothesis that inhibition of VEGF signaling in the maternal vasculature by high circulating sFlt1 may lead to preeclampsia-like signs/symptoms.…”

Section: Biology Of Antiangiogenic State In Preeclampsiamentioning

confidence: 99%

“…Although it was previously known that VEGF induces endothelial fenestrae in culture, 38 experimental data in genetically engineered mice that lack VEGF confirmed that endothelial fenestral density is regulated by constitutive expression of VEGF. 29 Therefore, it is not surprising that the microvascular damage in preeclampsia is largely concentrated in vasculature that constitutively express VEGF and that loss of endothelial fenestrae in preeclampsia is because of excess circulating sFlt1. Experimental studies in mice have also helped clarify that angiogenic imbalance and preeclampsia may be an important trigger for the clinical syndrome of peripartum cardiomyopathy.…”

Section: Biology Of Antiangiogenic State In Preeclampsiamentioning

confidence: 99%