Blockade of VEGF accelerates proteinuria, via decrease in nephrin expression in rat crescentic glomerulonephritis

Hara, Akinori; Wada, Takashi; Furuichi, Kengo; Sakai, Norihiko; Kawachi, Hiroshi; Shimizu, Fujio; Shibuya, M.; Matsushima, Kouji; Yokoyama, Hitoshi; Egashira, Kensuke; Kaneko, Shuichi

doi:10.1038/sj.ki.5000439

Cited by 92 publications

(65 citation statements)

References 40 publications

(26 reference statements)

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“…In this study, as in other studies (15,16), the expression of VEGF was markedly reduced in obstructed kidneys. Decrease in VEGF will cause loss of peritubular capillaries and fibrosis, which is destined to obstructed kidney.…”

Section: Discussionsupporting

confidence: 75%

Does Intervention in Utero Preserve the Obstructed Kidneys of Fetal Lambs? A Histological, Cytological, and Molecular Study

et al. 2009

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Ureteropelvic junction obstruction is a common cause of end-stage nephropathy in children. Our aim was to investigate whether relief of obstruction in utero can alleviate the development of nephropathy. A silastic tube was tied around the left superior segment ureter to induce unilateral partial ureteral obstruction in 22 fetal sheep at 75-85 d of gestation. Three weeks later, the tubes were removed to relieve the obstruction in 10 of the 22 lambs. A sham operation was performed on four fetuses (the control). At birth, the lambs were killed, and their kidneys were removed to study the changes in histology, podocytes, and expression of paired-box 2 (PAX2) and VEGF. In the obstructed kidneys, we observed cysts of various sizes in the cortex, fibrosis in the interstitial tissue, much decreased number of glomeruli, severe podocyte foot process fusion, and markedly increased PAX2 and decreased VEGF expressions. However, relief of obstruction preserved the number of glomeruli, significantly increased VEGF expression, reduced fusion of the podocyte foot processes, and restored expression of PAX2 to some extent. Thus, relief of obstruction in utero may prevent or attenuate the development of nephropathy in lambs. (1)]. At present, infants suffering from UPJO are either simply followed up or given surgical treatment based on hydronephrosis grade or renal function condition. However, Murer et al (2) found that the recovery from renal function injury even after the relief of UPJO was not assured in some children. Intervention in utero may help these patients. Chevalier et al (3) found that the relief of obstruction markedly reduced tubular atrophy and interstitial fibrosis in developing kidneys. However, Josephson et al (4) found that renal damage persisted despite very early efforts to remove obstruction. Because there is no consistent evidence linking recovery from renal damage to relief of UPJO in utero in humans, we decided to study this issue in fetal lambs.Podocytes are needed to maintain normal renal function; yet, they are easily injured by various abnormal situations. To our knowledge, changes in podocytes in obstructed kidneys have rarely been studied.Paired-box 2 (PAX2) is an important regulatory factor that functions early in the development of the kidney, and is restricted to the developing kidney. In damaged kidneys, PAX2 expression seems to be related to the proliferation of cystic renal epithelia, which is common in obstructed kidneys. VEGF is needed to maintain the renal blood vessel system. Decrease in VEGF will lead to fibrosis, another very common condition in obstructed kidneys.In this study, whether the relief of UPJO in utero in lambs would attenuate the development of nephropathy was investigated by observing changes in histology, podocytes, and expression of PAX2 and VEGF in kidneys after ureteral obstruction relief in utero. MATERIALS AND METHODSSevere unilateral partial ureteral obstruction was produced in 22 sheep fetuses at 75-85 d of gestation. In brief, open hysterotomy was perfo...

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Section: Discussionsupporting

confidence: 75%

Does Intervention in Utero Preserve the Obstructed Kidneys of Fetal Lambs? A Histological, Cytological, and Molecular Study

et al. 2009

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“…Inhibition of VEGF-A by a selective blocking antibody or the soluble VEGF receptor-soluble fms-like tyrosine kinase 1 has already been shown to worsen GN significantly. 17,28 Contrary to these reports, a decrease of VEGF was found to attenuate kidney failure in a model of reduced renal mass, 14 which led the authors to speculate that VEGF can have beneficial but also detrimental effects depending on the model itself and the starting point of treatment.…”

Section: Discussionmentioning

confidence: 49%

Differential Effects of Rapamycin in Anti-GBM Glomerulonephritis

Hochegger

Jansky²,

Soleiman³

et al. 2008

Journal of the American Society of Nephrology

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The immunosuppressive mammalian target of rapamycin inhibitor rapamycin is widely used in solidorgan transplantation, but the effect of rapamycin on kidney disease is controversial. This study evaluated the effect of rapamycin in the autologous phase of anti-glomerular basement membrane (anti-GBM) glomerulonephritis. Disease was induced by preimmunizing the animals with rabbit IgG 5 d before administration of rabbit anti-mouse GBM antiserum. When rapamycin was started on the day of immunization (group 1), mice were protected from glomerulonephritis, suggested by a dramatic decrease in albuminuria, influx of inflammatory cells, and Th1-cytokine expression in the kidneys. Activation of T cells and production of autologous mouse anti-rabbit IgG were also significantly reduced in rapamycin-treated animals. In contrast, when rapamycin was started 14 d after immunization (group 2), mice had a significant increase in albuminuria and renal infiltration of inflammatory cells compared with vehicle-treated animals, and there were no differences in T and B cell responses. A significant decrease in vascular endothelial growth factor-A and an increase in IL-6 were detected in kidneys of these rapamycin-treated mice. In conclusion, rapamycin has the potential to significantly reduce the B and T cell responses and thereby protect from glomerulonephritis when administered early in disease. Once disease is established, however, rapamycin seems to worsen glomerulonephritis by disturbing the endothelial cell/vascular endothelial growth factor system in the kidney.

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“…23 VEGF produced by podocytes is essential for the maintenance of the integrity of glomerular endothelial cells. 20,24 In addition, VEGF is also required for the maintenance of podocyte function and slit-diaphragm proteins, implying that podocyte-derived VEGF exerts both paracrine and autocrine effects.…”

Section: Discussionmentioning

confidence: 99%

Greater Sensitivity of Blood Pressure Than Renal Toxicity to Tyrosine Kinase Receptor Inhibition With Sunitinib

et al. 2015

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Abstract-Hypertension and renal injury are off-target effects of sunitinib, a tyrosine kinase receptor inhibitor used for the treatment of various tumor types. Importantly, these untoward effects are accompanied by activation of the endothelin system. Here, we set up a study to explore the dose dependency of these side effects. Normotensive Wistar Kyoto rats were exposed to 3 different doses of sunitinib or vehicle. After 8 days, rats were euthanized. Telemetrically measured blood pressure rose dose dependently, from 13 to 30 mm Hg. Proteinuria was present at all doses, but a rise in cystatin C occurred only at the intermediate and high doses. Compared with vehicle circulating endothelin-1 increased dose dependently, whereas 24-hour urinary endothelin excretion decreased. Light and electron microscopy revealed glomerular endotheliosis and ischemia with the intermediate and high doses of sunitinib but completely absent histological abnormalities with the low dose. Podocyte number per glomerular circumference did not change. Glomerular nephrin, Neph1, podocin, and endothelin-converting enzyme gene expression were downregulated in a dose-dependent manner.We conclude that the sunitinib-induced rise in blood pressure requires lower doses than its induction of renal function impairment and that functional changes in glomerular filtration barrier contribute to the occurrence of proteinuria, given the lack of histopathologic changes with the low dose of sunitinib. (Hypertension. 2015;66:543-549.

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Blockade of VEGF accelerates proteinuria, via decrease in nephrin expression in rat crescentic glomerulonephritis

Cited by 92 publications

References 40 publications

Does Intervention in Utero Preserve the Obstructed Kidneys of Fetal Lambs? A Histological, Cytological, and Molecular Study

Does Intervention in Utero Preserve the Obstructed Kidneys of Fetal Lambs? A Histological, Cytological, and Molecular Study

Differential Effects of Rapamycin in Anti-GBM Glomerulonephritis

Greater Sensitivity of Blood Pressure Than Renal Toxicity to Tyrosine Kinase Receptor Inhibition With Sunitinib

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