VEGF Inhibition and Renal Thrombotic Microangiopathy

Eremina, Vera; Jefferson, J. Ashley; Kowalewska, Jolanta; Hochster, Howard S.; Haas, Mark; Weisstuch, Joseph; Richardson, C. A.; Kopp, Jeffrey B.; Kabir, M. Golam; Backx, Peter H.; Gerber, Hans Peter; Ferrara, Napoleone; Barisoni, Laura; Alpers, Charles E.; Quaggin, Susan E.

doi:10.1056/nejmoa0707330

Cited by 1,373 publications

(1,153 citation statements)

References 19 publications

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“…It is interesting therefore that genetic deletion of vascular endothelial growth factor in podocytes only, is sufficient to trigger endothelial death and severe thrombotic glomerular injury. 49 Our studies confirmed the existence of a cell defined as fibrocyte, which did not express ␣SMA. Although we detected fibrocytes in injured kidney, spleen, and BM they were not detected in the circulation, suggesting that fibrocytes differentiate locally into coll1a1ϩ cells from either pre-existing cells or from circulating leukocytes such as a monocyte.…”

Section: Discussionsupporting

confidence: 77%

Pericytes and Perivascular Fibroblasts Are the Primary Source of Collagen-Producing Cells in Obstructive Fibrosis of the Kidney

Lin

Kisseleva

Brenner

et al. 2008

The American Journal of Pathology

766

856

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Understanding the origin of scar-producing myofibroblasts is vital in discerning the mechanisms by which fibrosis develops in response to inflammatory injury. Using a transgenic reporter mouse model expressing enhanced green fluorescent protein (GFP) under the regulation of the collagen type I, ␣ 1 (coll1a1) promoter and enhancers, we examined the origins of coll1a1-producing cells in the kidney. Here we show that in normal kidney, both podocytes and pericytes generate coll1a1 transcripts as detected by enhanced GFP, and that in fibrotic kidney, coll1a1-GFP expression accurately identifies myofibroblasts. To determine the contribution of circulating immune cells directly to scar production, wild-type mice, chimeric with bone marrow from coll-GFP mice, underwent ureteral obstruction to induce fibrosis. Histological examination of kidneys from these mice showed recruitment of small numbers of fibrocytes to the fibrotic kidney, but these fibrocytes made no significant contribution to interstitial fibrosis. Instead, using kinetic modeling and time course microscopy, we identified coll1a1-GFP-expressing pericytes as the major source of interstitial myofibroblasts in the fibrotic kidney. Our studies suggest that either vascular injury or vascular factors are the most likely triggers for pericyte migration and differentiation into myofibroblasts. Therefore, our results serve to refocus fibrosis research to injury of the vasculature rather than injury to the epithelium.

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Section: Discussionsupporting

confidence: 77%

Pericytes and Perivascular Fibroblasts Are the Primary Source of Collagen-Producing Cells in Obstructive Fibrosis of the Kidney

Lin

Kisseleva

Brenner

et al. 2008

The American Journal of Pathology

766

856

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“…In addition to the de novo identified podocyte-specific genes, genes that have been shown by genetic or functional studies to be causally involved in hereditary glomerular diseases and chronic progressive renal failure, including DACH1 (nanodissection rank 184) (Köttgen et al 2010), APOL1 (rank 185) (Genovese et al 2010;Kopp et al 2011), VEGFA (rank 247) (Eremina et al 2008;Köttgen et al 2010), and MYH9 (rank 260) (Kao et al 2008;Kopp et al 2008), were ranked highly by our method. During the preparation of this manuscript, MYO1E (rank 75) was reported to be associated with autosomal-recessive, glucocorticoid-resistant nephrotic syndrome (Mele et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Defining cell-type specificity at the transcriptional level in human disease

et al. 2013

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Cell-lineage–specific transcripts are essential for differentiated tissue function, implicated in hereditary organ failure, and mediate acquired chronic diseases. However, experimental identification of cell-lineage–specific genes in a genome-scale manner is infeasible for most solid human tissues. We developed the first genome-scale method to identify genes with cell-lineage–specific expression, even in lineages not separable by experimental microdissection. Our machine-learning–based approach leverages high-throughput data from tissue homogenates in a novel iterative statistical framework. We applied this method to chronic kidney disease and identified transcripts specific to podocytes, key cells in the glomerular filter responsible for hereditary and most acquired glomerular kidney disease. In a systematic evaluation of our predictions by immunohistochemistry, our in silico approach was significantly more accurate (65% accuracy in human) than predictions based on direct measurement of in vivo fluorescence-tagged murine podocytes (23%). Our method identified genes implicated as causal in hereditary glomerular disease and involved in molecular pathways of acquired and chronic renal diseases. Furthermore, based on expression analysis of human kidney disease biopsies, we demonstrated that expression of the podocyte genes identified by our approach is significantly related to the degree of renal impairment in patients. Our approach is broadly applicable to define lineage specificity in both cell physiology and human disease contexts. We provide a user-friendly website that enables researchers to apply this method to any cell-lineage or tissue of interest. Identified cell-lineage–specific transcripts are expected to play essential tissue-specific roles in organogenesis and disease and can provide starting points for the development of organ-specific diagnostics and therapies.

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“…Inhibition of VEGF or its receptors has been shown to lead to vessel regression in a number of tissues. In the kidney, VEGF neutralization resulted in glomerular endotheliosis and proteinuria (5)(6)(7). Vessel regression was also noted in the pancreas (8,9), trachea, thyroid, and small intestine (8).…”

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confidence: 99%

An essential role for RPE-derived soluble VEGF in the maintenance of the choriocapillaris

Saint‐Geniez

Kurihara

Sekiyama

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

464

335

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Clinical and experimental observations indicate a role for VEGF secreted by the retinal pigment epithelium (RPE) in the maintenance of the choriocapillaris (CC). VEGF in mice is produced as three isoforms, VEGF120, VEGF164, and VEGF188, that differ in their ability to bind heparan sulfate proteoglycan. RPE normally produces the more soluble isoforms, VEGF120 and VEGF164, but virtually no VEGF188, reflecting the fact that molecules secreted by the RPE must diffuse across Bruch's membrane (BrM) to reach the choriocapillaris. To determine the role of RPE-derived soluble VEGF on the choriocapillaris survival, we used mice that produce only VEGF188. VEGF188/188 mice exhibited normal choriocapillaris development. However, beginning at 7 months of age, we observed a progressive degeneration characterized by choriocapillaris atrophy, RPE and BrM abnormalities, culminating in areas of RPE loss and dramatic choroidal remodeling. Increased photoreceptor apoptosis in aged VEGF188/188 mice led to a decline in visual acuity as detected by electroretinogram (ERG). These changes are reminiscent of geographic atrophy (GA) and point to a role for RPE-derived VEGF in the maintenance of the choriocapillaris.age-related macular degeneration ͉ Bruch's membrane ͉ geographic atrophy ͉ retinal pigmented epithelium

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VEGF Inhibition and Renal Thrombotic Microangiopathy

Cited by 1,373 publications

References 19 publications

Pericytes and Perivascular Fibroblasts Are the Primary Source of Collagen-Producing Cells in Obstructive Fibrosis of the Kidney

Pericytes and Perivascular Fibroblasts Are the Primary Source of Collagen-Producing Cells in Obstructive Fibrosis of the Kidney

Defining cell-type specificity at the transcriptional level in human disease

An essential role for RPE-derived soluble VEGF in the maintenance of the choriocapillaris

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