Hypoxia-Induced Changes in Extracellular Matrix Metabolism in Renal Cells

Norman, Jill T.; Orphanides, C; García, Patricia L.; Fine, Leon G.

doi:10.1159/000020625

Cited by 79 publications

(54 citation statements)

References 39 publications

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“…Tubular cells under hypoxic conditions undergo epithelial-mesenchymal transdifferentiation to become myofibroblasts [19]. Hypoxia can also activate fibroblasts and change the extracellular matrix metabolism of resident renal cells [20,21]. pH is another factor that is implicated in cell injury under hypoxia.…”

Section: Hypoxia In the Pathogenesis Of Kidney Diseasementioning

confidence: 99%

Hypoxia and the HIF system in kidney disease

2007

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The kidney is sensitive to changes in oxygen delivery. This sensitivity has the merit of facilitating the kidneys in their adjustment of erythropoietin (EPO) production to changes in oxygen supply. The main determinant of EPO synthesis is the transcriptional activity of its gene in kidneys, which is related to local oxygen tensions. Regulation of EPO production is mediated by hypoxia-inducible factor (HIF). When local oxygen tension decreases, accumulated HIF binds to the key sequence of the EPO gene, the hypoxia-responsive element (HRE), and activates transcription of EPO. HIF consists of a constitutive β-subunit and one of alternative oxygen-regulated HIF α-subunits (HIF-1α, HIF-2α, and HIF-3α), and HIF-2α is responsible for erythropoietin production. However, the high sensitivity to changes in oxygen tension also makes the kidney prone to hypoxic injury. Severe energy depletion and subsequent activation of a number of critical alterations in metabolism occurs under hypoxic conditions. Hypoxia is also a profibrogenic stimulus. In addition to ischemic acute renal failure, hypoxia can also play a crucial role in the development of nephrotoxic acute kidney injury, radiocontrast nephropathy, and acute glomerulonephritis. Furthermore, accumulating evidence suggests that chronic hypoxia is a final common pathway to end-stage kidney failure in chronic kidney disease. Given that renal hypoxia has pivotal roles on the development and progression of both acute and chronic kidney disease, hypoxia can be a valid therapeutic target for chronic kidney disease. Activation of HIF leads to expression of a variety of adaptive genes in a coordinated manner. Studies utilizing HIF-stimulating agents proved efficacy in various kidney disease models, suggesting that HIF activation is an ideal target of future therapeutic approaches.

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Section: Hypoxia In the Pathogenesis Of Kidney Diseasementioning

confidence: 99%

Hypoxia and the HIF system in kidney disease

2007

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“…Hypoxia can activate fibroblasts, change extracellular matrix metabolism of resident renal cells, and lead to eventual fibrogenesis (68)(69)(70). Furthermore, Manotham from our group showed that mild hypoxia can induce transdifferentiation of cultured tubular cells into myofibroblasts (71).…”

Section: Mechanisms Of Tubulointerstitial Injury By Hypoxiamentioning

confidence: 99%

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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“…Despite intensive efforts to elucidate the pathomechanisms of chronic hypoxia on kidney damage, however, their complexity has hampered investigations and details remain scarce. Among others, mechanisms proposed to date include transdifferentiation (22), cell death (40 -42), production of extracellular matrix (26,27), and so on.Advances in proteomics technology offer promise to substantially improve our understanding and treatment of the molecular basis of disease. In particular, deciphering the alterations that occur in proteins between health and disease enables pharmaceutically relevant targets to be identified.…”

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confidence: 99%

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confidence: 99%

Chronic hypoxia aggravates renal injury via suppression of Cu/Zn-SOD: a proteomic analysis

Son¹,

Kojima²,

Inagi³

et al. 2008

American Journal of Physiology-Renal Physiology

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Son D, Kojima I, Inagi R, Matsumoto M, Fujita T, Nangaku M. Chronic hypoxia aggravates renal injury via suppression of Cu/Zn-SOD: a proteomic analysis. Am J Physiol Renal Physiol 294: F62-F72, 2008. First published October 24, 2007 doi:10.1152/ajprenal.00113.2007.-Accumulating evidence suggests a pathogenic role of chronic hypoxia in various kidney diseases. Chronic hypoxia in the kidney was induced by unilateral renal artery stenosis, followed 7 days later by observation of tubulointerstitial injury. Proteomic analysis of the hypoxic kidney found various altered proteins. Increased proteins included lipocortin-5, calgizzarin, ezrin, and transferrin, whereas the decreased proteins were ␣ 2u-globulin PGCL1, eukaryotic translation elongation factor 1␣ 2, and Cu/Zn superoxide dismutase (SOD1). Among these proteins, we focused on Cu/Zn-SOD, a crucial antioxidant. Western blot analysis and real-time quantitative PCR analysis confirmed the downregulation of Cu/Zn-SOD in the chronic hypoxic kidney. Furthermore, our laser capture microdissection system showed that the expression of Cu/Zn-SOD was predominant in the tubulointerstitium and was decreased by chronic hypoxia. The tubulointerstitial injury estimated by histology and immunohistochemical markers was ameliorated by tempol, a SOD mimetic. This amelioration was associated with a decrease in levels of the oxidative stress markers 4-hydroxyl-2-nonenal and nitrotyrosine. Our in vitro studies utilizing cultured tubular cells revealed a role of TNF-␣ in downregulation of Cu/Zn-SOD. Since the administration of anti-TNF-␣ antibody ameliorated Cu/Zn-SOD suppression, TNF-␣ seems to be one of the suppressants of Cu/Zn-SOD. In conclusion, our proteomic analysis revealed a decrease in Cu/Zn-SOD, at least partly by TNF-␣, in the chronic hypoxic kidney. This study, for the first time, uncovered maladaptive suppression of Cu/Zn-SOD as a mediator of a vicious cycle of oxidative stress and subsequent renal injury induced by chronic hypoxia. chronic kidney failure; oxidative stress ONCE RENAL DAMAGE REACHES a certain threshold, the progression of renal disease is consistent, irreversible and largely independent of the initial insult. The final common pathway in this process has been closely studied. The chronic hypoxia hypothesis, proposed by Fine et al. (11), emphasizes chronic ischemic damage in the tubulointerstitium as a final common pathway in end-stage kidney injury. Since its introduction, this fascinating hypothesis has been intensively investigated by many investigators (9,20,24). Despite intensive efforts to elucidate the pathomechanisms of chronic hypoxia on kidney damage, however, their complexity has hampered investigations and details remain scarce. Among others, mechanisms proposed to date include transdifferentiation (22), cell death (40 -42), production of extracellular matrix (26,27), and so on.Advances in proteomics technology offer promise to substantially improve our understanding and treatment of the molecular basis of disease. In particular, deciphering the a...

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Hypoxia-Induced Changes in Extracellular Matrix Metabolism in Renal Cells

Cited by 79 publications

References 39 publications

Hypoxia and the HIF system in kidney disease

Hypoxia and the HIF system in kidney disease

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

Chronic hypoxia aggravates renal injury via suppression of Cu/Zn-SOD: a proteomic analysis

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