Renal vascular endothelial growth factor in neonatal obstructive nephropathy. II. Exogenous VEGF

Burt, Laura E.; Forbes, Michael S.; Thornhill, Barbara A.; Kiley, Susan C.; Minor, Jordan J.; Chevalier, Robert L.

doi:10.1152/ajprenal.00294.2005

Cited by 10 publications

(15 citation statements)

References 30 publications

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“…In kidney injury induced by angiotensin II infusion followed by a high-salt diet, administration of VEGF-A 121 did not improve PTC rarefaction [79]. In addition, VEGF-A 121 treatment did not improve PTC rarefaction in neonatal mouse kidneys subjected to UUO [80], and systemic overexpression of a mutant form of VEGF-A that can bind only to VEGFR-2 but not to VEGFR-1 enhanced glomerular injury as well as interstitial fibrosis in mice with uninephrectomy [81]. Furthermore, the timing of angiogenic treatment is crucial.…”

Section: Considerations For Therapy To Limit Ptc Rarefaction In Ckdmentioning

confidence: 99%

Peritubular capillary rarefaction: a new therapeutic target in chronic kidney disease

2013

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Chronic kidney disease (CKD) is epidemic around the world and desparately needs new therapies. Peritubular capillary (PTC) rarefaction, along with interstitial fibrosis and tubular atorophy, is one of the major hallmarks of CKD and predicts renal outcome in patients with CKD. PTC endothelial cells (ECs) undergo apoptosis during CKD, leading to capillary loss, tissue hypoxia, and oxidant stress. Although the mechanisms of PTC rarefaction are not well understood, the process of PTC rarefaction depends on multiple events that happen during CKD. These events, which lead to an antiangiogenic environment, include deprivation of EC survival factors, increased production of vascular growth inhibitors, malfunction of ECs, dysfunction of endothelial progenitor cells, and loss of EC integrity via pericyte detachment from vasculature. In this review, we focus on major factors regulating angiogenesis and EC survival and describe roles of these factors in PTC rarefaction during CKD and possible therapeutic applications.

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Section: Considerations For Therapy To Limit Ptc Rarefaction In Ckdmentioning

confidence: 99%

Peritubular capillary rarefaction: a new therapeutic target in chronic kidney disease

2013

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“…These defects have not only been described in the kidney but also act systemically [67]. Simple administration of VEGF, therefore, is unlikely to be beneficial and in obstructive nephropathy, administration of VEGF actually worsened injury [68]. Intriguingly in some animal models of renal disease, anti-angiogenic drugs like thalidomide restore renovascular function [65, 69].…”

Section: The Two Faces Of Vegf and Angiogenesismentioning

confidence: 99%

Capillary rarefaction, hypoxia, VEGF and angiogenesis in chronic renal disease

Mayer

2011

Nephrology Dialysis Transplantation

108

112

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Tubulointerstitial hypoxia and peritubular capillary rarefaction are typical features of chronic progressive renal disease. In response to low oxygen supply, hypoxia-inducible factors (HIFs) are activated but until now, it is unclear if this increased expression leads to a stabilization of the disease process and thus is nephroprotective or contributes to interstitial fibrosis and/or tubular atrophy. This duality has also been described as far as vascular endothelial growth factor (VEGF), one of the major target genes of HIFs, is concerned. On the one hand, neoangiogenesis driven by VEGF, if intact, ameliorates hypoxia, on the other, VEGF is a potent pro-inflammatory mediator and neoangiogenesis, if defective because interference by other pathologies exaggerates injury. In summary, experimental data support the idea that dependent on timing and predominant pathology, hypoxia counter-regulatory factors exert beneficial or undesirable effects. Thus, before their therapeutic potential can be fully explored, a better way to characterize the clinical and pathophysiological situation in an individual patient is mandatory.

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“…caspases, intrinsic and extrinsic death pathway molecules, inhibitors of cyclin-dependent kinases p27 and p21, reactive oxygen species, and catalase) , the regulation of epithelial-mesenchymal transformation (hepatocyte growth factor, bone morphogenic protein 7, TGFβ-1, HIF-α and nestin) [40][41][42][43], hypoxic injury response (HIF-α) [44,45], cytokines and growth factors (TGFβ-1, EGF, PDGF-C, VEGF, IGF-1, connective tissue growth factor and TNF-α) [3,13,14,20,22,31,36,37,[46][47][48][49], and chemokines and chemoattractants (MCP-1, osteopontin, IL-1, ICAM-1, VCAM-1, angiotensin II and selectins) [13,[50][51][52][53][54][55][56][57][58]. This listing, impressive as it may appear, is by no means complete.…”

Section: Tubular Changesmentioning

confidence: 99%

Obstructive Uropathy

Truong¹,

Gaber

Eknoyan

2011

Contributions to Nephrology

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Chronic tubulointerstitial nephritis (TIN), characterized by tubular atrophy, interstitial fibrosis and inflammation, is a major prognostic determinant of chronic kidney disease, regardless of the original cause of the kidney disease. Understanding the pathogenesis of TIN has been hampered by the lack of an adequate experimental model. However, the demonstration that the renal lesions of obstructive uropathy induced by experimental urinary obstruction (UO) has provided an excellent model to study the pathogenesis of TIN in general and especially congenital obstructive nephropathy, the most common cause of pediatric end-stage renal disease. Since relief of experimental UO is technically possible, this model is particularly useful for studying the potential reversibility of TIN. Experimental UO is usually created by the unilateral ligation of a ureter. This induces progressive tubular epithelial cell injury, including apoptosis, proliferation, loss of differentiation and atrophy; interstitial inflammatory cell infiltrates composed predominantly of macrophages and T cells; and interstitial fibrosis characterized by an increase and activation of interstitial fibroblasts, deposition of extracellular matrix proteins and loss of peritubular capillaries. These changes collectively lead to progressive scarring and the loss of renal parenchyma and kidney function. The glomeruli and large blood vessels remain either normal or show mild changes later in the course of the disease. In addition to TIN, congenital obstructive nephropathy causes marked derangement of renal and glomerular development. Relief of UO does not seem to reverse TIN. In fact, the renal lesions of obstructive uropathy not only persist, but also progress long after UO is relieved in both adult and neonatal rats. The pathogenesis of UO-induced TIN has been well studied, at least in part because of the ready application of this model to mice, in which genetic manipulation including gene deletion or transfection of putative pathogenic molecules is technically feasible. Experimental UO immediately induces mechanical stretching of tubular epithelial cells and activates the renin-angiotensin system, leading to profound changes of the cells, including neo-expression of a large number of molecules which control cell cycle (e.g. caspases, intrinsic and extrinsic death pathway molecules, inhibitors of cyclin-dependent kinases p27 and p21, reactive oxygen species, and catalase), hypoxic response (HIF- α), epithelial-mesenchymal transformation (e.g. hepatocyte growth factor, bone morphogenic protein 7 and nestin), and the upregulation of cytokines and growth factors (e.g. TGFβ-1, EGF, PDGF, VEGF and TNF-α) as well as chemokines (MCP-1, osteopontin, IL-1, ICAM-1, VCAM-1 and selectins). Inflammatory cells are recruited immediately after UO, probably under the effect of the renin-angiotensin system and later by tubular cell-derived chemokines. Several chemokines and their receptors are also expressed by the infiltrating inflammatory cells, thereby augmenting the recruitm...

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Renal vascular endothelial growth factor in neonatal obstructive nephropathy. II. Exogenous VEGF

Cited by 10 publications

References 30 publications

Peritubular capillary rarefaction: a new therapeutic target in chronic kidney disease

Peritubular capillary rarefaction: a new therapeutic target in chronic kidney disease

Capillary rarefaction, hypoxia, VEGF and angiogenesis in chronic renal disease

Obstructive Uropathy

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