The Importance of Cellular VEGF Bioactivity in the Development of Glomerular Disease

Foster, Rebecca R.

doi:10.1159/000228078

Cited by 27 publications

(20 citation statements)

References 76 publications

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“…VEGF is mainly produced by podocytes and has a paracrine role to mediate angiogenesis beyond development via VEGF receptors on endothelial cells. 64 These findings are consistent with our studies to address the tissue-specific functions of Adora2b signaling. Indeed, we found in an Adora2b reporter mouse model that Adora2b expression is predominantly on the vasculature.…”

Section: Discussionsupporting

confidence: 91%

CD73-Dependent Generation of Adenosine and Endothelial Adora2b Signaling Attenuate Diabetic Nephropathy

Tak¹,

Ridyard²,

Kim

et al. 2014

Journal of the American Society of Nephrology

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Nucleotide phosphohydrolysis by the ecto-59-nucleotidase (CD73) is the main source for extracellular generation of adenosine. Extracellular adenosine subsequently signals through four distinct adenosine A receptors (Adora1, Adora2a, Adora2b, or Adora3). Here, we hypothesized a functional role for CD73-dependent generation and concomitant signaling of extracellular adenosine during diabetic nephropathy. CD73 transcript and protein levels were elevated in the kidneys of diabetic mice. Genetic deletion of CD73 was associated with more severe diabetic nephropathy, whereas treatment with soluble nucleotidase was therapeutic. Transcript levels of renal adenosine receptors showed a selective induction of Adora2b during diabetic nephropathy. In a transgenic reporter mouse, Adora2b expression localized to the vasculature and increased after treatment with streptozotocin. Adora2b 2/2 mice experienced more severe diabetic nephropathy, and studies in mice with tissue-specific deletion of Adora2b in tubular epithelia or vascular endothelia implicated endothelial Adora2b signaling in protection from diabetic nephropathy. Finally, treatment with a selective Adora2b agonist (BAY 60-6583) conveyed potent protection from diabetes-associated kidney disease. Taken together, these findings implicate CD73-dependent production of extracellular adenosine and endothelial Adora2b signaling in kidney protection during diabetic nephropathy.

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Section: Discussionsupporting

confidence: 91%

CD73-Dependent Generation of Adenosine and Endothelial Adora2b Signaling Attenuate Diabetic Nephropathy

Tak¹,

Ridyard²,

Kim

et al. 2014

Journal of the American Society of Nephrology

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“…VEGF (same as VEGF-A) is part of a family of VEGF proteins which includes VEGF-A, -B, -C, -D and placental-derived growth factor [61]. VEGF promotes angiogenesis, is highly expressed by podocytes, and is important in glomerular development [61,62,63].…”

Section: Pro-sclerotic Mediators Of Diabetic Nephropathy and Glut1mentioning

confidence: 99%

“…VEGF promotes angiogenesis, is highly expressed by podocytes, and is important in glomerular development [61,62,63]. VEGF is expressed in the adult kidney and has a paracrine role in glomerular endothelial cell signaling and fenestration formation [61,64]. VEGF signaling in diabetic nephropathy appears via the VEGF receptor type 2 [61,65,66,67].…”

Section: Pro-sclerotic Mediators Of Diabetic Nephropathy and Glut1mentioning

confidence: 99%

GLUT1 Regulation of the Pro-Sclerotic Mediators of Diabetic Nephropathy

et al. 2013

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Diabetic glomerulosclerosis is characterized by accumulation of extracellular matrix proteins, mesangial expansion, and tubulointerstitial fibrosis. Hyperglycemia accelerates development of the disease, a direct result of increased intracellular glucose availability. The facilitative glucose transporter GLUT1 mediates mesangial cell glucose flux which leads to activation of signaling cascades favoring glomerulosclerosis, including pathways mediated by angiotensin II (Ang II), transforming growth factor β (TGF-β), connective tissue growth factor (CTGF), and vascular endothelial growth factor (VEGF). Ang II has both hemodynamic and metabolic effects directly inducing GLUT1 and/or matrix protein synthesis through diacyl glycerol (DAG) or protein kinase C (PKC) induction, mesangial cell stretch, and/or through transactivation of the epidermal growth factor receptor, the platelet-derived growth factor receptor, and the insulin-like growth factor-1 receptor, all of which may stimulate GLUT1 synthesis via an ERK-mediated pathway. Conversely, inhibition of Ang II effects suppresses GLUT1 and cellular glucose uptake. GLUT1-mediated glucose flux leads to metabolism of glucose via glycolysis, with induction of DAG, PKC, TGF-β₁, CTGF and VEGF. VEGF in turn triggers both GLUT1 and matrix synthesis. New roles for GLUT1-mTOR and GLUT1-mechano-growth factor interactions in diabetic glomerulosclerosis have also recently been suggested. Recent mouse models confirmed roles for GLUT1 in vivo in stimulating glomerular growth factor expression, growth factor receptors and development of glomerulosclerosis. GLUT1 may therefore act in concert with cytokines and growth factors to induce diabetic glomerulosclerosis. Further clarification of the pathways involved may prove useful for the therapy of diabetic nephropathy. New directions for investigation are discussed.

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“…[3][4][5] The most important signal identified thus far is vascular endothelial growth factor A (VEGFA), which is highly expressed by podocytes, whereas its receptors are primarily found on glomerular endothelial cells. 6,7 Podocyte-specific haploinsufficiency for VEGFA during development results in glomerular endothelial lesions similar to pre-eclampsia, including loss of fenestrae and endothelial cell swelling.…”

mentioning

confidence: 99%

WT1-Dependent Sulfatase Expression Maintains the Normal Glomerular Filtration Barrier

Schumacher

Schlötzer‐Schrehardt²,

Karumanchi

et al. 2011

Journal of the American Society of Nephrology

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Paracrine signaling between podocytes and glomerular endothelial cells through vascular endothelial growth factor A (VEGFA) maintains a functional glomerular filtration barrier. Heparan sulfate proteoglycans (HSPGs), located on the cell surface or in the extracellular matrix, bind signaling molecules such as VEGFA and affect their local concentrations, but whether modulation of these moieties promotes normal crosstalk between podocytes and endothelial cells is unknown. Here, we found that the transcription factor Wilms' Tumor 1 (WT1) modulates VEGFA and FGF2 signaling by increasing the expression of the 6-O-endosulfatases Sulf1 and Sulf2, which remodel the heparan sulfate 6-O-sulfation pattern in the extracellular matrix. Mice deficient in both Sulf1 and Sulf2 developed age-dependent proteinuria as a result of ultrastructural abnormalities in podocytes and endothelial cells, a phenotype similar to that observed in children with WT1 mutations and in Wt1 ϩ/Ϫ mice. These kidney defects associated with a decreased distribution of VEGFA in the glomerular basement membrane and on endothelial cells. Collectively, these data suggest that WT1-dependent sulfatase expression plays a critical role in maintaining the glomerular filtration barrier by modulating the bioavailability of growth factors, thereby promoting normal crosstalk between podocytes and endothelial cells.

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The Importance of Cellular VEGF Bioactivity in the Development of Glomerular Disease

Cited by 27 publications

References 76 publications

CD73-Dependent Generation of Adenosine and Endothelial Adora2b Signaling Attenuate Diabetic Nephropathy

CD73-Dependent Generation of Adenosine and Endothelial Adora2b Signaling Attenuate Diabetic Nephropathy

GLUT1 Regulation of the Pro-Sclerotic Mediators of Diabetic Nephropathy

WT1-Dependent Sulfatase Expression Maintains the Normal Glomerular Filtration Barrier

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