Up-regulation of HIF in experimental acute renal failure: Evidence for a protective transcriptional response to hypoxia

Rosenberger, Christian; Heyman, Samuel N.; Rosen, Seymour; Shina, Ahuva; Goldfarb, Marina; Griethe, Wanja; Frei, Ulrich; Reinke, Petra; Bachmann, S.; Eckardt, Kai‐Uwe

doi:10.1111/j.1523-1755.2005.67110.x

Cited by 152 publications

(182 citation statements)

References 31 publications

(64 reference statements)

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“…Upregulation of the two HIF-␣ isoforms in the kidney by hypoxia was demonstrated in models of segmental renal infarction and radiocontrast nephropathy (68,69). Although cell-type specificity of HIF isoforms in these models was consistent with previous findings, temporal and spatial profiles of HIF activation were relatively complex, suggesting an important but complicated role of HIF in tissue preservation as a response to regional renal hypoxia.…”

Section: Hif As a Target For Drug Developmentsupporting

confidence: 77%

Chronic Hypoxia and Tubulointerstitial Injury

Nangaku

2006

Journal of the American Society of Nephrology

1,021

870

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Section: Hif As a Target For Drug Developmentsupporting

confidence: 77%

Chronic Hypoxia and Tubulointerstitial Injury

Nangaku

2006

Journal of the American Society of Nephrology

1,021

870

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“…In ATN, secondary to both ischemia-reperfusion and toxin injury, tubular cells become hypoxic (33). LDH is one of the genes up-regulated by hypoxia-inducible factor-1α (34), a transcription factor known to be increased in ATN (35,36). The increase in LDH activity, coupled with the expected increase in lactate concentration in the hypoxic tissue, will increase the degree of lactate labeling (37).…”

Section: Discussionmentioning

confidence: 99%

Magnetic resonance imaging with hyperpolarized [1,4- ¹³ C ₂ ]fumarate allows detection of early renal acute tubular necrosis

Clatworthy

Kettunen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

107

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Acute kidney injury (AKI) is a common and important medical problem, affecting 10% of hospitalized patients, and it is associated with significant morbidity and mortality. The most frequent cause of AKI is acute tubular necrosis (ATN). Current imaging techniques and biomarkers do not allow ATN to be reliably differentiated from important differential diagnoses, such as acute glomerulonephritis (GN). We investigated whether 13 C magnetic resonance spectroscopic imaging (MRSI) might allow the noninvasive diagnosis of ATN. C]lactate ratio showed substantial variability and was not significantly decreased in animals with ATN or increased in animals with GN. In conclusion, MRSI of hyperpolarized [1,[4][5][6][7][8][9][10][11][12][13] C 2 ]fumarate allows the detection of early tubular necrosis and its distinction from glomerular inflammation in murine models. This technique may have the potential to identify a window of therapeutic opportunity in which emerging therapies might be applied to patients with ATN, reducing the need for acute dialysis with its attendant morbidity and cost.hyperpolarization | MRI

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“…Studies on a multi-insult rat model of ARF combining the application of contrast medium with nitric oxide synthase and cyclooxygenase inhibition showed widespread induction of HIF in the outer and inner medulla that was initiated within 10 min, reached the highest levels at 2 h, and diminished 8 h, to 24 h thereafter [25]. HIF isoforms were expressed in a cell type-specific fashion with HIF-1α in tubular and HIF-2α in interstitial and endothelial cells.…”

Section: Acute Kidney Injurymentioning

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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Up-regulation of HIF in experimental acute renal failure: Evidence for a protective transcriptional response to hypoxia

Abstract: A complex pattern of HIF activation appears to play an important role in tissue preservation as a response to regional renal hypoxia. The limited capacity of mTAL cells for HIF activation may explain their susceptibility to injury.

Cited by 152 publications

References 31 publications

Chronic Hypoxia and Tubulointerstitial Injury

Chronic Hypoxia and Tubulointerstitial Injury

Magnetic resonance imaging with hyperpolarized [1,4- ¹³ C ₂ ]fumarate allows detection of early renal acute tubular necrosis

Hypoxia and the HIF system in kidney disease

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Up-regulation of HIF in experimental acute renal failure: Evidence for a protective transcriptional response to hypoxia

Abstract: A complex pattern of HIF activation appears to play an important role in tissue preservation as a response to regional renal hypoxia. The limited capacity of mTAL cells for HIF activation may explain their susceptibility to injury.

Cited by 152 publications

References 31 publications

Chronic Hypoxia and Tubulointerstitial Injury

Chronic Hypoxia and Tubulointerstitial Injury

Magnetic resonance imaging with hyperpolarized [1,4- 13 C 2 ]fumarate allows detection of early renal acute tubular necrosis

Hypoxia and the HIF system in kidney disease

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Magnetic resonance imaging with hyperpolarized [1,4- ¹³ C ₂ ]fumarate allows detection of early renal acute tubular necrosis