VEGF165 mediates glomerular endothelial repair

Ostendorf, Tammo; Kunter, Uta; Eitner, Frank; Loos, Anneke; Regele, Heinz; Kerjaschki, Dontscho; Henninger, Dwight; Janjić, Nebojša; Floege, Jürgen

doi:10.1172/jci6740

Cited by 282 publications

(256 citation statements)

References 54 publications

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“…36,37 In this case, VEGF works in association with NO to maintain normal structure and function of the glomerular basement membrane, 40 stimulate glomerular repair, and inhibit proteinuria. 41 This pathway could explain the amelioration of proteinuria and hypertension in the PRE þ MgSO 4 group in the current study. Additionally, the vasodilatory effect of NO may augment the inhibitory effect of MgSO 4 on the vascular tone and peripheral vascular resistance, leading to decreased BP and increased renal blood flow.…”

Section: Discussionmentioning

confidence: 53%

Magnesium sulfate therapy of preeclampsia: an old tool with new mechanism of action and prospect in management and prophylaxis

Korish

2012

Hypertens Res

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A disturbed balance between angiogenic and antiangiogenic growth factors is a highly accepted mechanism in the pathogenesis of pregnancy-induced hypertension and proteinuria, which is clinically known as preeclampsia (PE). We investigated the effect of magnesium sulfate (MgSO 4 ) therapy on vascular endothelial growth factor (VEGF), placental growth factor (PlGF), nitric oxide (NO) metabolites, soluble fm-like tyrosine kinase-1 (sFlt-1) and endoglin levels in PE rats and the effect of this treatment on the feto-maternal outcome. The PE group showed hypertension, proteinuria and decreased number and weight of live pups relative to the control group. This result was associated with increased sFlt-1, VEGF receptor-2 (VEGFR-2), VEGFR-3 and endoglin levels but decreased NO metabolites. MgSO 4 therapy ameliorated systolic hypertension and proteinuria and decreased sFlt-1, VEGFR-2, VEGFR-3 and endoglin levels but increased NO metabolites in the treated group. Physiological and biochemical changes and improved pup weight and viability were observed in the treated group. The vasodilator action of MgSO 4 and increased NO production are expected to increase placental blood flow and help fetal nutrition and development. Relief of placental ischemia decreases the production of antiangiogenic growth factors and restores the bioavailability of angiogenic factors (PlGF and VEGF). These changes resulted in better fetal outcome and an improved clinical picture of PE. These findings are promising and encourage further study of the mechanism of action of MgSO 4 to support its widespread use in the prevention and management of the etiopathological changes underlying the vast majority of the manifestations and complications of PE.

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Section: Discussionmentioning

confidence: 53%

Magnesium sulfate therapy of preeclampsia: an old tool with new mechanism of action and prospect in management and prophylaxis

Korish

2012

Hypertens Res

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“…How did the capillaries disappear? In conjunction with the gradual loss of GBM folds, the capillaries lost their abutments to the GBM and obviously underwent a kind of controlled decomposition by -as known from previous studies (21,22) -endothelial cell apoptosis, which led to a dramatic reduction in capillary length but preserved the vascular lining. From the opposite process, the sprouting of new capillaries (see below), it may be supposed that the loss of the narrow association to podocytes was relevant.…”

Section: Damage Developmentmentioning

confidence: 76%

Pathways to Recovery and Loss of Nephrons in Anti-Thy-1 Nephritis

Kriz¹,

Hähnel²,

Hosser³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. The present histopathologic study of anti-Thy-1.1 models of mesangioproliferative glomerulonephritis in rats provides a structural analysis of damage development and of pathways to recovery and to nephron loss. As long as the disease remains confined to the endocapillary compartment, the damage may be resolved or recover with a mesangial scar. Irreversible lesions with loss of nephrons emerge from extracapillary processes with crucial involvement of podocytes, leading to tuft adhesions to Bowman's capsule (BC) and subsequent crescent formation. Two mechanisms appeared to be responsible: (1) Epithelial cell proliferation at BC and the urinary orifice and (2) misdirected filtration and filtrate spreading on the outer aspect of the nephron. Both may lead to obstruction of the tubule, disconnection from the glomerulus, and subsequent degeneration of the entire nephron. No evidence emerged to suggest that the kind of focal interstitial proliferation associated with the degeneration of injured nephrons was harmful to a neighboring healthy nephron.Glomerular diseases starting with mesangiolysis have a high probability of recovery. However, not all nephrons recover; some always undergo destruction; we therefore raised the following questions: (1) what is the crucial stage of damage that determines the subsequent recovery or progression and (2) what are the sequences of events leading either to the restitution or to the degeneration of the respective nephron? Thus, our primary question was not why a nephron degenerated or recovered but how these outcomes were achieved. A glomerulus, and all the more a nephron, are both complex structures; we therefore wanted to analyze to which extent the loss and, on the other hand, the reestablishment of the higher order structure were decisive for damage progression and recovery, respectively.The most common models used to study mesangiolysis and damage development starting therefrom are those that induce mesangial cell lysis with antibodies against the Thy 1.1 antigen of mesangial cells; the resulting disease is generally referred to as anti-Thy-1 nephritis. The classical experiments were performed either with polyclonal antibodies (1,2) or with the monoclonal antibody OX-7 (3). More recently, the monoclonal antibody 1-22-3 (4) has been shown to produce more severe damage. Administration of these antibodies in rats leads to a brisk complement-dependent lysis of the mesangial cells followed by the development of a mesangioproliferative glomerulonephritis.We used both the OX-7 and the 1-22-3 antibodies in two originally separate studies. Because disease development was more or less identical in both models, we combined both studies. This permitted us to analyze complete pathways of damage development and to provide step-by-step sequences of events leading from mesangiolysis via various intermediate stages to either the recovery or loss of a nephron. We think that these results are of considerable general interest when asking how nephrons degenerate in chronic renal disease. M...

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“…However, recent data also suggest that VEGF has a major role in glomerular diseases (25,46,61). In an experimental model of nephritis, blockade of VEGF in vivo was found to increase intrarenal apoptosis, impair glomerular capillary repair, and result in proteinuria (48). In humans, blockade of VEGF with anti-VEGF for the treatment of metastatic renal cancer was found to result in proteinuria (67), and it has been proposed that the use of high concentrations of anti-VEGF may be limited by this "renal" side effect.…”

mentioning

confidence: 99%