scholarly journals Herniation of the tuft with outgrowth of vessels through the glomerular entrance in diabetic nephropathy damages the juxtaglomerular apparatus

2019 ◽  
Vol 317 (2) ◽  
pp. F399-F410 ◽  
Author(s):  
Jana Löwen ◽  
Elisabeth Gröne ◽  
Hermann-Josef Gröne ◽  
Wilhelm Kriz
Keyword(s):  
Diabetic Nephropathy ◽  
Juxtaglomerular Apparatus ◽  
Tubuloglomerular Feedback ◽  
Mrna Levels ◽  
Vascular Endothelial ◽  
The Matrix ◽  
Matrix Expansion ◽  
Advanced Stages ◽  
Endothelial Growth Factor ◽  
Aberrant Vessels

As shown in our previous paper (Kriz W, Löwen J, Federico G, van den Born J, Gröne E, Gröne HJ. Am J Physiol Renal Physiol 312: F1101–F1111, 2017), mesangial matrix expansion in diabetic nephropathy (DN) results for a major part from the accumulation of worn-out undegraded glomerular basement membrane material. Here, based on the reevaluation of >900 biopsies of DN, we show that this process continues with the progression of the disease finally leading to the herniation of the matrix-overloaded tuft through the glomerular entrance to the outside. This leads to severe changes in the glomerular surroundings, including a dissociation of the juxtaglomerular apparatus with displacement of the macula densa. The herniation is associated with a prominent outgrowth of glomerular vessels from the tuft. Mostly, these aberrant vessels are an abnormal type of arteriole with frequent intramural insudations of plasma. They spread into glomerular surroundings extending in intertubular and periglomerular spaces. Their formation is associated with elevated mRNA levels of vascular endothelial growth factor-A, angiopoietins 1 and 2, and the corresponding receptors. Functionally, these processes seem to compromise tubuloglomerular feedback-related functions and may be one factor why Na+-glucose cotransporter-2 inhibitors are not effective in advanced stages of DN.

1. Targeting Slit2-Robo Signaling as a Novel Therapy for Diabetic Nephropathy

2018 ◽  
Author(s):  
Lauren Chan
Keyword(s):  
Diabetic Nephropathy ◽  
Diabetic Rats ◽  
Male Rats ◽  
Mrna Levels ◽  
Vascular Endothelial ◽  
Novel Therapy ◽  
Capillary Growth ◽  
Life Threatening ◽  
And Gender ◽  
Endothelial Growth Factor

Diabetes is a chronic disease that can lead to life-threatening complications such as diabetic nephropathy (DN). An early manifestation of DN is hyperfiltration, a predictor of poor renal outcomes. Hyperfiltration is partly driven by capillary growth (angiogenesis) within the glomeruli, the filtration units of the kidney. A major stimulus for diabetic glomerular angiogenesis is vascular endothelial growth factor (VEGF). VEGF neutralization blocks hyperfiltration in diabetes, but VEGF blockade itself can lead to renal injury. Endothelial cells express Robo1 and Robo4, which serve as receptors for the secreted ligand Slit2. Robo4 activation by Slit2 inhibits endothelial angiogenesis, whereas Slit2 activation of Robo1 promotes angiogenesis.In search of novel therapies for diabetes-induced glomerular hyperfiltration, we hypothesized that diabetes affects the expression of Slit2 and/or its Robo receptors. We further tested whether Slit2 administration attenuates VEGF-driven diabetic capillary growth.Diabetes was induced by injection of streptozocin (STZ) in male rats. Age- and gender-matched non-diabetic rats were followed as controls. 3 weeks later, kidneys were harvested from both groups, and the expression of Slit2, Robo1 and Robo4 analyzed. In parallel, male diabetic rats were randomized to receive Slit2 or saline injections every 3 days. After 3 weeks, kidney filtration and capillary growth were measured in both groups.Diabetes was associated with a reduction in kidney Robo4 expression, whereas Slit2 and Robo1 mRNA levels were unchanged. Slit2 administration attenuated the diabetes-induced rise in kidney filtration and glomerular capillary growth. Our results suggest that targeting Slit2-Robo signalling may have therapeutic importance for early diabetic nephropathy.

149 EXPRESSION OF ANGIOGENIC FACTORS AND THEIR MAJOR RECEPTORS IN THE SHEEP PLACENTA THROUGHOUT THE EARLY PREGNANCY

2006 ◽  
Vol 18 (2) ◽  
pp. 182
Author(s):  
P. P. Borowicz ◽  
D. A. Redmer ◽  
A. T. Grazul-Bilska ◽  
G. Ptak ◽  
P. Loi ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Growth Factor Receptor ◽  
Angiogenic Factors ◽  
Mrna Levels ◽  
Vascular Endothelial ◽  
Fibroblast Growth ◽  
Mrna Concentration ◽  
Endothelial Growth Factor

Embryonic losses are high in mammals, with more than 30% of fertilized eggs not resulting in an offspring. The development of the placenta is critical for normal fetal growth and development as it provides for exchange of respiratory gases, nutrients, and wastes between the fetal and maternal systems. Placental vascular development determines the rate of placental blood flow, which is a primary determinant of placental function. Recent studies suggest that vascular endothelial growth factor (VEGF), its receptors (VEGFR), along with angiopoietins (Ang-1 and Ang-2) and their common receptor Tie-2, are major placental angiogenic factors, along with fibroblast growth factor-2 (FGF-2) and its receptor (FGFR). To evaluate the patterns of placental expression of these factors during early placental development, gravid uteri were obtained from ewes (n = 6 per day) on Days 12, 18, 24, 30, and 40 of gestation (day of mating = Day 0). At slaughter the uterine and embryonic tissues were weighed and representative samples of utero-placenta (CAR - caruncle, maternal placenta; ICAR - intracarunclar, endometrium; FM, fetal membranes) were snap frozen on dry ice and analyzed for relative mRNA levels by real-time RT-PCR (ABI Prism 7000, Sequence Detection System, Applied Biosystems, Monza, Italy) of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-1 (VEGFR-1), vascular endothelial growth factor receptor-2 (VEGFR-2), angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), receptor for both angiopoietins (Tie-2), fibroblast growth factor-2 (FGF-2), and fibroblast growth factor receptor (FGFR). The data were analyzed by nonlinear procedures using proc reg of SAS (SAS Institute, Inc., Cary, NC, USA). In CAR, the data showed the exponential increase from Days 12 to 40 in mRNA expression for VEGFR-1 (P < 0.0004; 0.04398e0.08794�day), VEGFR-2 (P < 0.01; 0.119208e0.06537�day), Ang-1 (P < 0.005; 0.00488e0.10881�day), Ang-2 (P < 0.0001; 0.01591e0.07864�day), Tie-2 (P < 0.03; 0.00488e0.06852�day), and FGFR (P < 0.08; 0.24577e0.04721�day). In the CAR, we also observed an exponential decrease in mRNA concentration for VEGF (P < 0.05; 28.193e-1.0719�day). In ICAR, we observed an exponential increase in mRNA concentration for VEGF (P < 0.05; 1.11685e0.06865�day), VEGFR-1 (P < 0.07; 0.09853e0.0383�day), Ang-1 (P < 0.09; 0.009318e0.05711�day), and Ang-2 (P < 0.004; 0.012647e0.09973�day). For FM, no changes in mRNA levels were observed from Days 12 to 40, but levels of all mRNAs were similar to those in CAR and ICAR. Based on the patterns of mRNA expression, these data indicate that these angiogenic factors may play an important role in early placental angiogenesis in sheep. This work was supported by NIH grant HL64141 to LPR and DAR.

scholarly journals Expression of vascular endothelial growth factor in response to high glucose in rat mesangial cells

2000 ◽  
Vol 165 (3) ◽  
pp. 617-624 ◽  
Author(s):  
NH Kim ◽  
HH Jung ◽  
DR Cha ◽  
DS Choi
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Diabetic Nephropathy ◽  
Growth Factor ◽  
High Glucose ◽  
Mesangial Cells ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Protein Levels ◽  
Calphostin C ◽  
Endothelial Growth Factor

Diabetic nephropathy associated with hyperglycemia is characterized by glomerular hyperfiltration and endothelial dysfunction. Vascular endothelial growth factor (VEGF) is known to be primarily involved in neoangiogenesis and increased endothelial permeability. The purpose of this study was to investigate VEGF expression in response to high glucose in rat cultured mesangial cells and to identify its signal pathway via protein kinase C (PKC). Rat mesangial cells were cultured with different concentrations of glucose: normal (5 mM d-glucose), medium (15 mM d-glucose) and high (30 mm d-glucose). Calphostin-C as a PKC inhibitor and phorbol myristate acetate (PMA) as a PKC downregulator were instillated into culture media to evaluate the role of PKC in mediating the glucose-induced increase in VEGF expression. High glucose increased expression of VEGF at the mRNA and protein levels, identified by semi-quantitative RT-PCR and western blotting, within 3 h and in a time- and glucose concentration-dependent manner. Calphostin-C and PMA inhibited glucose-induced increases in VEGF expression at the mRNA and protein levels. In conclusion, high glucose can directly increase VEGF expression in rat mesangial cells via a PKC-dependent mechanism. These results suggest that VEGF could be a potential mediator of glomerular hyperfiltration and proteinuria in diabetic nephropathy.

scholarly journals Synergistic Up-Regulation of Vascular Endothelial Growth Factor (VEGF) Expression in Macrophages by Adenosine A2AReceptor Agonists and Endotoxin Involves Transcriptional Regulation via the Hypoxia Response Element in the VEGF Promoter

2007 ◽  
Vol 18 (1) ◽  
pp. 14-23 ◽  
Author(s):  
Madhuri Ramanathan ◽  
Grace Pinhal-Enfield ◽  
Irene Hao ◽  
Samuel Joseph Leibovich
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Transcriptional Regulation ◽  
Growth Factor ◽  
Promoter Activity ◽  
Luciferase Reporter ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Endothelial Growth Factor

Macrophages are an important source of vascular endothelial growth factor (VEGF). Adenosine A2Areceptor (A2AR) agonists with Toll-like receptor (TLR) 2, 4, 7, and 9 agonists synergistically induce macrophage VEGF expression. We show here using VEGF promoter-luciferase reporter constructs that the TLR4 agonist Escherichia coli lipopolysaccharide (LPS) and the A2AR agonists NECA and CGS21680 synergistically augment VEGF transcription in macrophages and that the HRE in the VEGF promoter is essential for this transcription. We examined whether LPS and/or NECA induce HIF-1α expression. HIF-1α mRNA levels were increased in LPS-treated macrophages in an NF-κB–dependent manner; NECA strongly increased these levels in an A2AR-dependent manner. LPS induced luciferase expression from a HIF-1α promoter-luciferase construct in an A2AR-independent manner. Further stimulation with NECA did not increase HIF-1α promoter activity, indicating that the A2AR-dependent increase in HIF-1α mRNA is post-transcriptional. LPS/NECA treatment also increased HIF-1α protein and DNA binding levels. Deletion of putative NF-κB–binding sites from the VEGF promoter did not affect LPS/NECA-induced VEGF promoter activity, suggesting that NF-κB is not directly involved in VEGF transcription. Taken together, these data indicate that LPS/NECA-induced VEGF expression involves transcriptional regulation of the VEGF promoter by HIF-1α through the HRE. HIF-1α is transcriptionally induced by LPS and post-transcriptionally up-regulated in an A2AR-dependent manner.

scholarly journals VEGF-A-Cleavage by FSAP and Inhibition of Neo-Vascularization

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1396 ◽  
Author(s):  
Özgür Uslu ◽  
Joerg Herold ◽  
Sandip M. Kanse
Keyword(s):  
Growth Factor ◽  
Tissue Injury ◽  
Factor Vii ◽  
Endothelial Cell Proliferation ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
The Matrix ◽  
Endothelial Growth Factor

Alternative splicing leads to the secretion of multiple forms of vascular endothelial growth factor-A (VEGF-A) that differ in their activity profiles with respect to neovascularization. FSAP (factor VII activating protease) is the zymogen form of a plasma protease that is activated (FSAPa) upon tissue injury via the release of histones. The purpose of the study was to determine if FSAPa regulates VEGF-A activity in vitro and in vivo. FSAP bound to VEGF165, but not VEGF121, and VEGF165 was cleaved in its neuropilin/proteoglycan binding domain. VEGF165 cleavage did not alter its binding to VEGF receptors but diminished its binding to neuropilin. The stimulatory effects of VEGF165 on endothelial cell proliferation, migration, and signal transduction were not altered by FSAP. Similarly, proliferation of VEGF receptor-expressing BAF3 cells, in response to VEGF165, was not modulated by FSAP. In the mouse matrigel model of angiogenesis, FSAP decreased the ability of VEGF165, basic fibroblast growth factor (bFGF), and their combination, to induce neovascularization. Lack of endogenous FSAP in mice did not influence neovascularization. Thus, FSAP inhibited VEGF165-mediated angiogenesis in the matrigel model in vivo, where VEGF’s interaction with the matrix and its diffusion are important.

scholarly journals C-Abl Is Required for the Development of Hyperoxia-Induced Retinopathy

2001 ◽  
Vol 193 (12) ◽  
pp. 1383-1392 ◽  
Author(s):  
Irene Nunes ◽  
Rosemary D. Higgins ◽  
Lucia Zanetta ◽  
Peter Shamamian ◽  
Stephen P. Goff
Keyword(s):  
Mrna Expression ◽  
Retinal Neovascularization ◽  
Mrna Levels ◽  
Vascular Endothelial ◽  
Wild Type ◽  
Vegf Mrna ◽  
Nonreceptor Tyrosine Kinase ◽  
Kinase C ◽  
Endothelial Growth Factor ◽  
Inspired Oxygen

The requirement for the nonreceptor tyrosine kinase c-abl in the pathogenesis of retinopathy of prematurity (ROP) was examined using the mouse model for ROP and c-abl–deficient mice. Hyperoxia-induced retinal neovascularization was observed in wild-type and heterozygous mice but animals that were homozygous null for c-abl did not develop a vasoproliferative retinopathy in response to hyperoxia. Two gene products, endothelin-1 (ET-1) and vascular endothelial growth factor (VEGF), have been implicated in the pathogenesis of ROP. The mRNA expression of ET-1 and VEGF was assessed in mice maintained in normoxia and in hyperoxia-exposed mice. ET-1 mRNA levels were unchanged in wild-type mice throughout the hyperoxia treatment, suggesting that ET-1 mRNA expression is not regulated by the increase in inspired oxygen. In wild-type mice maintained in room air, VEGF mRNA levels rose threefold from postnatal day 6 (P6) to P17. When wild-type mice were treated with the hyperoxia regimen, a fivefold decrease in VEGF mRNA expression was observed from P7 to P16. However, retinal VEGF expression in hyperoxia-treated homozygous null mice did not decrease and remained at control levels. These data suggest that c-abl is required for the hyperoxia-induced retinal neovascularization and hyperoxia-induced decrease in VEGF mRNA levels.

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