The pivotal role of VEGF on glomerular macrophage infiltration in advanced diabetic nephropathy

Sato, Waichi; Kosugi, Tomoki; Zhang, Li; Roncal, Carmen; Heinig, Marcelo; Campbell-Thompson, Martha; Yuzawa, Yukio; Atkinson, Mark A.; Grant, Maria B.; Croker, Byron P.; Nakagawa, Takahiko

doi:10.1038/labinvest.2008.60

Cited by 58 publications

(49 citation statements)

References 37 publications

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“…Caution is advised in interpreting these data, however, because recent studies have challenged the existence of this epithelial-mesenchymal transition in kidney disease. 45 In opposition to our predictions, and despite the fact that inflammatory reactions after VEGF-stimulation are thought to be attributed to VEGFR1, not VEGFR2, 11,12 selective VEGFR2 stimulation elevated macrophage infiltration as assessed by F4/80 and CD68 staining, regardless of eNOS expression, The renal macrophage infiltration observed in the present study was unlikely to be due to direct VEGFR2 stimulation, but probably was due to an indirect effect from other cytokines that may be expressed in injured kidneys.…”

Section: Discussioncontrasting

confidence: 99%

“…Tubulointerstitial injury was assessed by immunohistochemistry (IHC) with goat anti-human collagen III (SouthernBiotech, Birmingham, AL) and rat antimouse F4/80 (Serotec, Oxford, UK) which detects a subtype of macrophages present predominately in the interstitium. 11,25 Phenotypic changes in tubular epithelial cells were evaluated using rabbit anti-human ␣-SMA (Abcam, Cambridge, MA) and rabbit anti-human transforming growth factor ␤1 (TGF-␤1) (Santa Cruz Biotechnology, Santa Cruz, CA). Rabbit antimouse collagen IV (Chemicon International, Temecula, CA), rabbit anti-human fibronectin (Sigma-Aldrich, St. Louis, MO), and mouse anti-human CD68 (Abcam; performed on frozen kidney), a marker of macrophage subtypes predominantly expressed in glomeruli, 11,25 were used to evaluate glomerular injury.…”

Section: Ihcmentioning

confidence: 99%

“…11,25 Phenotypic changes in tubular epithelial cells were evaluated using rabbit anti-human ␣-SMA (Abcam, Cambridge, MA) and rabbit anti-human transforming growth factor ␤1 (TGF-␤1) (Santa Cruz Biotechnology, Santa Cruz, CA). Rabbit antimouse collagen IV (Chemicon International, Temecula, CA), rabbit anti-human fibronectin (Sigma-Aldrich, St. Louis, MO), and mouse anti-human CD68 (Abcam; performed on frozen kidney), a marker of macrophage subtypes predominantly expressed in glomeruli, 11,25 were used to evaluate glomerular injury. For vascular assessment of angiogenic responses, capillary endothelial cells were detected by a rabbit anti-rat thrombomodulin 26 and rabbit monoclonal human VEGFR2 (Cell Signaling Technology, Danvers, MA).…”

Section: Ihcmentioning

confidence: 99%

“…Consistent with this hypothesis, diabetic nephropathy is worsened in the setting of endothelial NO deficiency and the effects of VEGF-A to induce angiogenesis and inflammation are enhanced in this setting. 10,11 The actions of VEGF-A are mediated through its two receptors, Flt-1 (VEGFR1) and Flk-1 (VEGFR2). VEGFR1 is involved in the inflammatory response by stimulating macrophage chemotaxis, 11,12 as well as vascular permeability and vessel stabilization.…”

mentioning

confidence: 99%

“…10,11 The actions of VEGF-A are mediated through its two receptors, Flt-1 (VEGFR1) and Flk-1 (VEGFR2). VEGFR1 is involved in the inflammatory response by stimulating macrophage chemotaxis, 11,12 as well as vascular permeability and vessel stabilization. 13,14 In contrast, VEGFR2 mediates angiogenesis 15 and reduces blood pressure.…”

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Selective Stimulation of VEGFR2 Accelerates Progressive Renal Disease

Sato

Tanabe

Kosugi

et al. 2011

The American Journal of Pathology

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Vascular endothelial growth factor A (VEGF-A) can play both beneficial and deleterious roles in renal diseases, where its specific function might be determined by nitric oxide bioavailability. The complexity of VEGF-A in renal disease could in part be accounted for by the distinct roles of its two receptors; VEGFR1 is involved in the inflammatory responses, whereas VEGFR2 predominantly mediates angiogenesis. Because nondiabetic chronic renal disease is associated with capillary loss, we hypothesized that selective stimulation of VEGFR2 could be beneficial in this setting. However, VEGFR2 activation may be deleterious in the presence of nitric oxide deficiency. We systematically overexpressed a mutant form of VEGF-A binding only VEGFR2 (Flk-sel) using an adeno-associated virus-1 vector in wild-type and eNOS knockout mice and then induced renal injury by uninephrectomy. Flksel treatment increased angiogenesis and lowered blood pressure in both mouse types. Flk-sel overexpression caused mesangial injury with increased proliferation associated with elevated expression of PDGF, PDGF-␤ receptor, and VEGFR2; this effect was greater in eNOS knockout than in wild-type mice. Flk-sel also induced tubulointerstitial injury, with some tubular epithelial cells expressing ␣-smooth muscle actin, indicating a phenotypic evolution toward myofibroblasts. In conclusion, prestimulation of VEGFR2 can potentiate subsequent renal injury in mice, an effect enhanced in the setting of nitric oxide deficiency.

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Section: Discussioncontrasting

confidence: 99%

Section: Ihcmentioning

confidence: 99%

Section: Ihcmentioning

confidence: 99%

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Selective Stimulation of VEGFR2 Accelerates Progressive Renal Disease

Sato

Tanabe

Kosugi

et al. 2011

The American Journal of Pathology

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Endothelial nitric oxide synthase inhibits the development of autoimmune‐mediated vasculitis in mice

Schoeb¹,

Jarmi²,

Hicks³

et al. 2012

Arthritis & Rheumatism

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Objective Many different genes or mediators have been implicated in promoting the development of vasculitis, although little is known regarding the mechanisms that normally act to suppress lesion formation. eNOS (NOS3) has been shown to inhibit vascular inflammation in many different model systems, but its roles in the pathogenesis of vasculitis have not been elucidated. The aim of this study was to determine the functions of eNOS in the initiation and progression of vasculitic lesion formation. Methods Nos3 mutant MRL/MpJ-Faslpr mice were generated and comprehensively evaluated and compared to controls for the development of autoimmune disease, including vasculitic lesion formation and glomerulonephritis. Results Nos3−/− MRL/MpJ-Faslpr mice had accelerated onset and increased incidence of renal vasculitis compared to Nos3+/+ controls. In contrast, no significant differences in severity of glomerulonephritis were observed between groups. Vasculitis was also observed in eNOS deficient mice in other organs, including increased expression in the lung. Ultrastructural analyses of renal lesions revealed the presence of electron dense deposits in affected arteries, while IgG, IgA, and C3 deposition was observed in some vessels in Nos3−/− kidneys. In addition, eNOS deficient mice showed increased levels of circulating IgG-IgA immune complexes at 20 weeks of age compared to Nos3+/+ MRL/MpJ-Faslpr and Nos3−/− C57BL/6 mice. Conclusion These findings strongly indicate that eNOS serves as a negative regulator of vasculitis in MRL/MpJ-Faslpr mice, and further suggest that NO produced by this enzyme may be critical for inhibiting lesion formation and vascular damage in human vasculitic diseases.

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Hyperglycemia and mechanical stress: Targeting the renal podocyte

Lewko

Stępiński

2009

Journal Cellular Physiology

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Hyperglycemia and deriving from glomerular hypertension mechanical stress are the key factors underlying pathogenesis of diabetic nephropathy (DN). Multiple direct and secondary effects of both these factors are mediated by complex signaling pathways with extensive interactions. The common signaling pathways stimulated by high glucose and mechanical insult may act in an additive manner, thereby accelerating the cell damage. Podocytes, the cells covering the outer aspect of glomerular basement membrane (GBM), are subjected not only to the load of filtered glucose but also to diverse mechanical forces. Bulging into the Bowman's space, they have no support from the apical side, which makes them particularly susceptible to the effects of mechanical strain. Both high glucose and mechanical stress may impair the protein systems anchoring the podocyte foot processes in GBM, therefore blunting resistance of these cells to mechanical forces. Modulation by these factors of expression and activity of numerous structural and functional proteins results in the (auto)inflammatory responses, dysfunction, apoptosis or necrosis of the podocytes. Loss of the podocytes is irreversible due to their inability to proliferate and to replenish damaged cells. Podocytes are injured early in the course of DN, which, most likely, underlies further glomerular and renal damage in diabetes. This review summarizes the effects of elevated glucose and mechanical stress that seem to be involved in podocyte impairment in diabetes, with particular focus on the possible interactions between these factors.

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The pivotal role of VEGF on glomerular macrophage infiltration in advanced diabetic nephropathy

Cited by 58 publications

References 37 publications

Selective Stimulation of VEGFR2 Accelerates Progressive Renal Disease

Selective Stimulation of VEGFR2 Accelerates Progressive Renal Disease

Endothelial nitric oxide synthase inhibits the development of autoimmune‐mediated vasculitis in mice

Hyperglycemia and mechanical stress: Targeting the renal podocyte

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