Vascular endothelial growth factor accelerates renal recovery in experimental thrombotic microangiopathy

Kim, Yoon-Goo; Suga, Shin-ichi; Kang, Duk‐Hee; Jefferson, J. Ashley; Mazzali, Marilda; Gordon, Katherine; Matsui, Katsuyuki; Breiteneder-Geleff, Silvana; Shankland, Stuart J.; Hughes, Jeremy; Kerjaschki, Dontscho; Schreiner, George F.; Johnson, Richard J.

doi:10.1046/j.1523-1755.2000.00422.x

Cited by 197 publications

(137 citation statements)

References 23 publications

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“…Administration of VEGF also restores the number of peritubular capillaries and protects the kidney in the thrombotic microangiopathy model (88,89). These beneficial effects of VEGF were probably mediated by preservation of the capillary endothelium and were associated with partial reversal of the impaired angiogenesis.…”

Section: Treatment Targeting Hypoxic Tubulointerstitial Damagementioning

confidence: 93%

Mechanisms of Tubulointerstitial Injury in the Kidney: Final Common Pathways to End-stage Renal Failure

2004

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There are many different glomerular disorders, including glomerulonephritis, diabetic nephropathy, and hypertensive nephrosclerosis. However, once glomerular damage reaches a certain threshold, the progression of renal disease is consistent and irreversible. Recent studies emphasized the crucial role of tubulointerstitial injury as a mediator of progression of kidney disease. One common mechanism that leads to renal failure via tubulointerstitial injury is massive proteinuria. Accumulating evidence suggests critical effects of filtered macromolecules on tubular cells, including lysosomal rupture, energy depletion, and tubular injury directly induced by specific components such as complement components. Another common mechanism is chronic hypoxia in the tubulointerstitium. Tubulointerstitial damage results in the loss of peritubular capillaries, impairing blood flow delivery. Interstitial fibrosis also impairs oxygen diffusion and supply to tubular cells. This induces chronic hypoxia in this compartment, rendering a vicious cycle. Development of novel therapeutic approaches against these final common pathways will enable us to target any types of renal disease. (Internal Medicine 43: 9-17, 2004)

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Section: Treatment Targeting Hypoxic Tubulointerstitial Damagementioning

confidence: 93%

Mechanisms of Tubulointerstitial Injury in the Kidney: Final Common Pathways to End-stage Renal Failure

2004

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“…ED-1-positive cells were counted in 20 randomly selected fields including both cortex and outer medulla with an ϫ10 objective. Peritubular capillary loss was analyzed using rarefaction index as previously reported (9). Briefly, it was determined by counting the numbers of squares in 10 ϫ 10 grids that did not contain JG-12-positive peritubular capillary staining, in at least ten non-overlapping sequential fields in the outer medulla.…”

Section: Renal Histologic Analysesmentioning

confidence: 99%

Induction of Renoprotective Gene Expression by Cobalt Ameliorates Ischemic Injury of the Kidney in Rats

Matsumoto¹,

Makino

Tanaka³

et al. 2003

Journal of the American Society of Nephrology

237

171

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Abstract. Hypoxia in the tubulointerstitium has been thought to play pivotal roles in the pathophysiology of acute renal failure and the progression of chronic kidney disease. Pre-induction of hypoxia-inducible and renoprotective gene expression may protect subsequent ischemic injury. This study evaluated the efficacy of cobalt, which inhibits HIF-1 degradation and increases the expression level of hypoxia-related genes, in an acute ischemic tubulointerstitial injury model of rats. Ischemic renal injury was induced by 45-min clamping of renal pedicles with contralateral nephrectomy. Elevation of serum creatinine and morphologic injury after the ischemic insult was observed. Administration of cobalt chloride afforded striking functional improvement (mean Ϯ SEM creatinine in mg/dl: Co treatment group, 2.14 Ϯ 1.21; control, 3.69 Ϯ 1.43; P Ͻ 0.05) associated with amelioration of tubulointerstitial damage. Cobalt treatment also reduced macrophage infiltration significantly. In the kidney of rats treated with cobalt, mRNA levels of several genes that serve for tissue protection, such as HO-1, EPO, Glut-1, and VEGF, were increased before ischemic injury. Upregulation of HO-1 by cobalt was confirmed at the protein level. Subcutaneous injection of cobalt also ameliorated ischemic injury, which was associated with upregulation of renal HIF-1␣ protein expression. These results suggest that protection against hypoxic tubulointerstitial injury by cobalt administration is mediated by induction of renoprotective gene expression. HIF induction is one possible and attractive explanation for the observed effects.Hypoxia contributes significantly to the pathophysiology of major categories of human disease, including myocardial and cerebral ischemia, cancer, congenital heart disease, and chronic obstructive pulmonary disease. In the kidney, ischemic injury leads to acute renal failure (ARF). Although renal function after episodes of ARF is thought to be restored, initial ischemic injury is associated with high morbidity and mortality. Furthermore, hypoxia is crucial in progression of chronic renal disease (1). There is growing evidence that reduction of peritubular capillary density coincides with loss of renal function and results in progressive renal failure, implying a role of hypoxia in tubulointerstitial damage, which leads to eventual kidney failure (2).Improvement of the ability of organs to tolerate ischemic injury would be beneficial in case of hypoxia. An exposure to hypoxic environment is known to stimulate genes that play roles in the adaptation to oxygen deficiency. A category of them includes proteins involved in regulating glucose uptake and glucose metabolism, which allow maintaining energy synthesis under hypoxic condition. The other category includes proteins involved in angiogenesis and erythropoiesis, which increase blood vessel density and blood oxygen-carrying capacity.Many processes of adaptation to hypoxia are mediated by hypoxia inducible factor (HIF), which is a master regulator of genes activated by low o...

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“…8 -10 Moreover, administration of the proangiogenic growth factor vascular endothelial growth factor (VEGF) has recently been shown to enhance glomerular capillary repair and accelerate renal recovery or prevent progression of renal disease in several experimental models. 11,12 Insight into the "healing" process of the glomerular microvasculature may enhance our understanding of the pathophysiology of progressive renal failure and provide novel approaches for treatment of renal disease.…”

mentioning

confidence: 99%

Bone-Marrow-Derived Cells Contribute to Glomerular Endothelial Repair in Experimental Glomerulonephritis

Rookmaaker

Smits

Tolboom

et al. 2003

The American Journal of Pathology

160

121

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Glomerular endothelial injury plays an important role in the pathogenesis of renal diseases and is centrally involved in renal disease progression. Glomerular endothelial repair may help maintain renal function. We examined whether bone-marrow (BM)-derived cells contribute to glomerular repair. A rat allogenic BM transplant model was used to allow tracing of BM-derived cells using a donor major histocompatibility complex class-I specific mAb. In glomeruli of chimeric rats we identified a small number of donor-BM-derived endothelial and mesangial cells, which increased in a time-dependent manner. Induction of anti-Thy-1.1-glomerulonephritis (transient mesangial and secondary glomerular endothelial injury) caused a significant, more than fourfold increase in the number of BM-derived glomerular endothelial cells at day 7 after anti-Thy-1.1 injection compared to chimeric rats without glomerular injury. The level of BM-derived endothelial cells remained high at day 28. We also observed a more than sevenfold increase in the number of BM-derived mesangial cells at day 28. BM-derived endothelial and mesangial cells were fully integrated in the glomerular structure. Our data show that BM-derived cells participate in glomerular endothelial and mesangial cell turnover and contribute to microvascular repair. These findings provide novel insights into the pathogenesis of renal disease and suggest a potential role for stem cell therapy.

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Vascular endothelial growth factor accelerates renal recovery in experimental thrombotic microangiopathy

Abstract: VEGF accelerates renal recovery in this experimental model of TMA. These studies suggest that angiogenic growth factors may provide a new therapeutic strategy for diseases associated with endothelial cell injury.

Cited by 197 publications

References 23 publications

Mechanisms of Tubulointerstitial Injury in the Kidney: Final Common Pathways to End-stage Renal Failure

Mechanisms of Tubulointerstitial Injury in the Kidney: Final Common Pathways to End-stage Renal Failure

Induction of Renoprotective Gene Expression by Cobalt Ameliorates Ischemic Injury of the Kidney in Rats

Bone-Marrow-Derived Cells Contribute to Glomerular Endothelial Repair in Experimental Glomerulonephritis

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