Vascular endothelial growth factor is an essential molecule for mouse kidney development: glomerulogenesis and nephrogenesis.

Kitamoto, Yasunori; Tokunaga, Hiroshi; Tomita, Kimio

doi:10.1172/jci119416

Cited by 279 publications

(206 citation statements)

References 21 publications

(31 reference statements)

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“…Recently many types of knockout and transgenic analyses in mice have been instrumental in identifying molecules important for kidney development, especially in the early stages of nephron development. [3][4][5] However, our knowledge is still limited concerning molecules of importance in late-stage glomerulogenesis 7,13,14 and in the steady-state function of the mature glomerulus. Improved methods for glomerulus isolation would constitute an important step toward further molecular analysis of glomerular development and function.…”

Section: Discussionmentioning

confidence: 99%

A New Method for Large Scale Isolation of Kidney Glomeruli from Mice

Takemoto¹,

Asker²,

Gerhardt³

et al. 2002

The American Journal of Pathology

467

417

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Here we report a new isolation method for mouse glomeruli. The method is fast and simple and allows for the isolation of virtually all glomeruli present in the adult mouse kidney with minimal contamination of nonglomerular cells. Mice were perfused through the heart with magnetic 4.5-m diameter Dynabeads. Kidneys were minced into small pieces, digested by collagenase, filtered, and collected using a magnet. The number of glomeruli retrieved from one adult mouse was 20,131 ؎ 4699 (mean ؎ SD, n ‫؍‬ 14) with a purity of 97.5 ؎ 1.7%. The isolated glomeruli retained intact morphology, as confirmed by light and electron microscopy, as well as intact mRNA integrity, as confirmed by Northern blot analysis. The method was applicable also to newborn mice, which allows for the isolation of immature developmental stage glomeruli. This method makes feasible transcript profiling and proteomic analysis of the developing, healthy and diseased mouse glomerulus. As the genome projects are near completion, 1,2 an important step in the functional analysis of genome data are the determination of transcriptomes corresponding to specific cellular functions and states of differentiation. Such analyses require methods allowing for the isolation of highly homogenous population of cells and/or microorgans from in vivo situations. One such microorgan is the kidney glomerulus. Glomeruli constitute ϳ10% of whole kidney tissues and are unique structures of microvasculature mainly made up of three highly specialized cell types; fenestrated endothelial cells, mesangial cells, and podocytes. These cell types together with the glomerular basement membrane form the permeable barrier across which blood is filtered to produce primary urine. During the past decade several gene products have been shown to play essential roles in glomerulus development, 3-5 function, and pathology. 6 However, our knowledge of the molecular mechanisms governing glomerulus morphogenesis and development of the specialized features of its individual cells is still very limited. An obvious difficulty in addressing these issues stems from the low abundance of the glomerulus cells and the inability of the glomerulus cell types to retain their differentiated features in cell culture. Podocytes, for example, make up less than 2% of kidney tissues. Although endothelial cells and pericytes exist outside the glomerulus, their phenotype within the glomerulus is quite distinct from related cells elsewhere. 7 We describe a new protocol for the isolation of glomeruli from mice. The protocol is fast and allows for the isolation of virtually all glomeruli present in a mouse kidney at 97% purity. The method thus allows for transcript profiling and proteomic analysis of the glomerulus using standard procedures.

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Section: Discussionmentioning

confidence: 99%

A New Method for Large Scale Isolation of Kidney Glomeruli from Mice

Takemoto¹,

Asker²,

Gerhardt³

et al. 2002

The American Journal of Pathology

467

417

View full text Add to dashboard Cite

show abstract

“…6 Angiogenesis during embryologic growth and development requires functioning VEGF; without it, death ensues. 7 Postnatal VEGF blockade results in stunted growth, increased mortality due to renal failure, and impaired organ development, 8,9 while experimental blockade in juvenile primates causes ovarian failure and stunted growth due to chondrocyte failure within the epiphyseal growth plates. 10 In adults, VEGF infusion stimulates microvascular perfusion in patients with severe coronary artery disease and ischemic limbs.…”

mentioning

confidence: 99%

The Expanding Role of Vascular Endothelial Growth Factor Inhibitors in Ophthalmology

Stewart

2012

Mayo Clinic Proceedings

166

105

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Vascular endothelial growth factor (VEGF) plays an important role in both physiologic and pathologic angiogenesis and contributes to increased permeability across both the blood-retinal and blood-brain barriers. After 2 decades of extensive research into the VEGF families and receptors, specific molecules have been targeted for drug development, and several medications have received US Food and Drug Administration approval. Bevacizumab, a full-length antibody against VEGF approved for the intravenous treatment of advanced carcinomas, has been used extensively in ophthalmology for exudative age-related macular degeneration, diabetic retinopathy, retinal vein occlusions, retinopathy of prematurity, and other chorioretinal vascular disorders. Pegaptanib and ranibizumab have been developed specifically for intraocular use, whereas the soon-to-be-introduced aflibercept (VEGF Trap-Eye) is moving through clinical trials for both intraocular and systemic use. Although these drugs exhibit excellent safety profiles, ocular and systemic complications, particularly thromboembolic events, remain a concern in patients receiving therapy. Patients experiencing adverse events that may be related to VEGF suppression should be carefully evaluated by both the ophthalmologist and the medical physician to reassess the need for intraocular therapy and explore the feasibility of changing medications. For this review a search of PubMed from January 1, 1985 through April 15, 2011, was performed using the following terms (or combination of terms): vascular endothelial growth factors, VEGF, age-related macular degeneration, diabetic retinopathy, retina vein occlusions, retinopathy of prematurity, intravitreal injections, bevacizumab, ranibizumab, and VEGF Trap. Studies were limited to those published in English. Other articles were identified from bibliographies of retrieved articles and archives of the author.

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“…In mice, renal capillaries surrounding proximal tubules in the cortex be-come prominent from the late fetal period whereas vasa rectae mature 1 to 3 weeks postnatally. 1 Genetic and pharmacological strategies have proven that VEGF-A is important in glomerular capillary growth, 9,10 and transgenic expression of EphB4 receptor, a gene expressed in developing kidney vessels, 11 perturbs glomerular arteriole patterning. 12 Mutant mice have implicated platelet-derived growth factor B (PDGFB) signaling in mesangial morphogenesis 13,14 and also ␣8 integrin in morphogenesis of peritubular capillaries.…”

mentioning

confidence: 99%

Dysmorphogenesis of Kidney Cortical Peritubular Capillaries in Angiopoietin-2-Deficient Mice

Pitera¹,

Woolf²,

Gale³

et al. 2004

The American Journal of Pathology

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Angiopoietin-2 (Ang-2) modulates Tie-2 receptor activation. In mouse kidney maturation, Ang-2 is expressed in arteries, with lower levels in tubules, whereas Tie-2 is expressed by endothelia. We hypothesized that Ang-2 deficiency disrupts kidney vessel patterning. The normal renal cortical peritubular space contains fenestrated capillaries, which have few pericytes; they receive water and solutes which proximal tubules reclaim from the glomerular filtrate. In wild-type neonates, ␣ smooth muscle actin (␣SMA), platelet-derived growth factor receptor ␤ (PDGFR␤), and desmin-expressing cells were not prominent in this compartment. In Ang-2 null mutants, ␣SMA, desmin, and PDGFR␤ prominently immunolocalized in cortical peritubular locations. Some ␣SMA-positive cells were closely associated with CD31-and Tie-2-positive peritubular capillary endothelia, and some of the ␣SMA-positive cells expressed PDGFR␤, desmin, and neural/glial cell 2 (NG2), consistent with a pericyte-like identity. Immunoblotting suggested an increase of total and tyrosine-phosphorylated Tie-2 proteins in null mutant versus wild-type kidneys, and electron microscopy confirmed disorganized capillaries and adjacent cells in cortical peritubular spaces in mutant neonate kidneys. Hence, Ang-2 deficiency causes dysmorphogenesis of cortical peritubular capillaries, with adjacent cells expressing pericyte-like markers; we speculate the latter effect is caused by disturbed paracrine signaling between endothelial and surrounding mesenchymal precursor cells.

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Vascular endothelial growth factor is an essential molecule for mouse kidney development: glomerulogenesis and nephrogenesis.

Cited by 279 publications

References 21 publications

A New Method for Large Scale Isolation of Kidney Glomeruli from Mice

A New Method for Large Scale Isolation of Kidney Glomeruli from Mice

The Expanding Role of Vascular Endothelial Growth Factor Inhibitors in Ophthalmology

Dysmorphogenesis of Kidney Cortical Peritubular Capillaries in Angiopoietin-2-Deficient Mice

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