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      Role of Hypoxia in the Pathogenesis of Renal Disease

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          Despite a high overall oxygen supply, the tissue oxygen tensions in the kidney are comparatively low and render the kidneys prone to hypoxic injury. However, the role of hypoxia in the pathogenesis of different types of renal disease remains incompletely understood. The importance of hypoxic cell injury is most obvious in renal vascular disease, in which occlusion of the renal artery or one of its branches can induce tissue necrosis. In acute renal failure, circumstantial evidence suggests that hypoxic injury to the renal medulla plays a significant role. In addition, chronically impaired oxygenation may also be an important factor in the progression of chronic renal disease. Destruction of the glomerular capillaries leads to hypoperfusion of the peritubular interstitium. Moreover, in focal disease, a compensatory increase in perfusion of other glomeruli may increase flow and pressure in peritubular capillaries derived from their vasa efferentia which could be a cause of microvascular injury. The interstitial capillary density is reduced in chronic renal disease, and results of animal experiments suggest that this is due to an imbalance in the expression of pro- and antiangiogenic factors. Besides its essential role in energy generation, oxygen is increasingly recognized as an important regulator of cellular functions. Hypoxia induces specific genes through increased expression of hypoxia-inducible transcription factors (HIF). Different HIF isoforms have recently been shown to be inducible in glomerular, tubular, and interstitial cells of the kidney. While the majority of HIF-dependent genes confer protection against hypoxia, hypoxia-inducible gene expression has been suggested to contribute also to increased interstitial matrix deposition.

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          Most cited references 6

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          Hypoxia of the renal medulla--its implications for disease.

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            Hypoxia promotes fibrogenesis in human renal fibroblasts.

            The mechanisms underlying progressive renal fibrosis are unknown, but the common association of fibrosis and microvascular loss suggests that hypoxia per se may be a fibrogenic stimulus. To determine whether human renal fibroblasts (HRFs), the primary matrix-producing cells in the tubulointerstitium, possess oxygen-sensitive responses relevant to fibrogenesis, cells were exposed to 1% O2 in vitro. Hypoxia simultaneously stimulated extracellular matrix synthesis and suppressed turnover with increased production of collagen alpha1(I) (Coll-I), decreased expression of collagenase, and increased tissue inhibitor of metalloproteinase (TIMP)-1. These effects are time dependent, require new RNA and protein synthesis, and are specific to hypoxia. The changes in Coll-I and TIMP-1 gene expression involve a heme-protein O2 sensor and protein kinase- and tyrosine kinase-mediated signaling. Although hypoxia induced transforming growth factor-beta1 (TGF-beta1), neutralizing anti-TGF-beta1-antibody did not block hypoxia-induced Coll-I and TIMP-1 mRNA expression. Furthermore, hypoxic-cell conditioned-medium had no effect on the expression of these mRNAs in naive fibroblasts, suggesting direct effects on gene transcription. Transient transfections identified a hypoxia response element (HRE) in the TIMP-1 promoter and demonstrated HIF-1-dependent promoter activation by decreased ambient pO2. These data suggest that hypoxia co-ordinately up-regulates matrix production and decreases turnover in renal fibroblasts. The results support a role for hypoxia in the pathogenesis of fibrosis and provide evidence for novel, direct hypoxic effects on the expression of genes involved in fibrogenesis.
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              Vascular endothelial growth factor (VEGF121) protects rats from renal infarction in thrombotic microangiopathy.

              Renal thrombotic microangiopathy, typified by the hemolytic uremic syndrome, is associated with endothelial cell injury in which the presence of cortical necrosis, extensive glomerular involvement, and arterial occlusive lesions correlates with a poor clinical outcome. We hypothesized that the endothelial survival factor vascular endothelial growth factor (VEGF) may provide protection. Severe, necrotizing, thrombotic microangiopathy was induced in rats by the renal artery perfusion of antiglomerular endothelial antibody, followed by the administration of VEGF or vehicle, and renal injury was evaluated. Control rats developed severe glomerular and tubulointerstitial injury with extensive renal necrosis. The administration of VEGF significantly reduced the necrosis, preserved the glomerular endothelium and arterioles, and reduced the number of apoptotic cells in glomeruli (at 4 hours) and in the tubulointerstitium (at 4 days). The prosurvival effect of VEGF for endothelium may relate in part to the ability of VEGF to protect endothelial cells from factor-induced apoptosis, as demonstrated for tumor necrosis factor-alpha (TNF-alpha), which was shown to be up-regulated through the course of this model of renal microangiopathy. Endothelial nitric oxide synthase expression was preserved in VEGF-treated rats compared with its marked decrease in the surviving glomeruli and interstitium of the antibody-treated rats that did not receive VEGF. VEGF protects against renal necrosis in this model of thrombotic microangiopathy. This protection may be mediated by maintaining endothelial nitric oxide production and/or preventing endothelial cell death.

                Author and article information

                Blood Purif
                Blood Purification
                S. Karger AG
                05 June 2003
                : 21
                : 3
                : 253-257
                Department of Nephrology and Medical Intensive Care, Charité, Humboldt University, Berlin, Germany
                70698 Blood Purif 2003;21:253–257
                © 2003 S. Karger AG, Basel

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                Page count
                Figures: 2, References: 20, Pages: 5
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                Proceedings of the 20th ISBP Meeting


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