Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α

Yu, Aimee Y.; Shimoda, Larissa A.; Iyer, Narayan V.; Huso, David L.; Sun, Xiaohuan; McWilliams, Rita; Beaty, Terri H.; Sham, James S.K.; Wiener, Charles; Sylvester, J. J.; Semenza, Gregg L.

doi:10.1172/jci5912

Cited by 606 publications

(500 citation statements)

References 49 publications

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“…Mice with a homozygous deletion of HIF-1␣ die in utero as a result of multiple developmental abnormalities (21,46). Heterozygous mice lacking one HIF-1␣ allele demonstrate reduced hypoxia-induced activation of HIF-1 and develop less severe hypoxic pulmonary hypertension and right ventricular hypertrophy, compared with wild-type mice (47), suggesting that HIF-1␣ activity might indeed contribute to some pathophysiologic changes observed during chronic hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Functional Activation of Heat Shock Factor and Hypoxia-Inducible Factor in the Kidney

Eickelberg¹,

Seebach²,

Riordan³

et al. 2002

Journal of the American Society of Nephrology

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Abstract. Renal ischemia is the result of a complex series of events, including decreases in oxygen supply (hypoxia) and the availability of cellular energy (ATP depletion). In this study, the functional activation of two stress-responsive transcription factors, i.e., heat shock factor-1 (HSF-1) and hypoxia-inducible factor-1 (HIF-1), in the kidney was assessed. When rats were subjected to 45 min of renal ischemia, electrophoretic mobility shift assays of kidney nuclear extracts revealed rapid activation of both HIF-1 and HSF. Western blot analyses further demonstrated that this activation resulted in increased expression of the HSF and HIF-1 target genes heat shock protein-72 and heme oxygenase-1, respectively. Whether hypoxia or ATP depletion alone could produce similar activation patterns in vitro was then investigated. Renal epithelial LLC-PK 1 cells were subjected to either ATP depletion (0.1 M antimycin A and glucose deprivation) or hypoxia (1% O 2 ). After ATP depletion, HSF was rapidly activated (within 30 min), whereas HIF-1 was unaffected. In contrast, hypoxia led to the activation of HIF-1 but not HSF. Hypoxic activation of HIF-1 was observed within 30 min and persisted for 4 h, whereas no HSF activation was detected even with prolonged periods of hypoxia. HIF-1 was transcriptionally active in LLC-PK 1 cells, as demonstrated by luciferase reporter gene assays using the vascular endothelial growth factor promoter or a synthetic promoter construct containing three hypoxia-inducible elements. Interestingly, intracellular ATP levels were not affected by hypoxia but were significantly reduced by ATP depletion. These findings suggest that HIF-1 is activated specifically by decreased O 2 concentrations and not by reduced ATP levels alone. In contrast, HSF is activated primarily by metabolic stresses associated with ATP depletion and not by isolated O 2 deprivation. In vivo, the two transcription factors are simultaneously activated during renal ischemia, which might account for observed differences between in vivo and in vitro epithelial cell injury and repair. Selective modulation of either pathway might therefore be of potential interest for modification of the response of the kidney to ischemia, as well as the processes involved in recovery from ischemia.

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Section: Discussionmentioning

confidence: 99%

Functional Activation of Heat Shock Factor and Hypoxia-Inducible Factor in the Kidney

Eickelberg¹,

Seebach²,

Riordan³

et al. 2002

Journal of the American Society of Nephrology

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“…Although HIF-1α +/− heterozygous mice develop normally, partial HIF-1α deficiency results in significantly impaired responses to hypoxia and ischemia (1,7,15,26). The administration of 200 ppm of acrylamide in drinking water for 1 wk did not cause distal limb weakness in WT HIF-1α +/+ mice, whereas this dose was sufficient to cause significant distal limb weakness in HIF-1α +/− littermate mice (Fig.…”

Section: No Donor Administration Prevents Axonal Degeneration Ex Vivomentioning

confidence: 92%

“…Information regarding derivation and characterization of these mice is available at http://jaxmice.jax.org. The generation of HIF-1α +/− mice on a C57BL/6J × 129 genetic background has been described previously (26,41). Offspring of HIF-1α +/+ and HIF-1α +/− matings were genotyped by PCR, and 8-wk-old male HIF-1α +/− and HIF-1α +/+ littermates were studied.…”

Section: Methodsmentioning

confidence: 99%

Nitric oxide prevents axonal degeneration by inducing HIF-1–dependent expression of erythropoietin

Keswani

Bosch–Marcé

Reed

et al. 2011

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

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Nitric oxide (NO) is a signaling molecule that can trigger adaptive (physiological) or maladaptive (pathological) responses to stress stimuli in a context-dependent manner. We have previously reported that NO may signal axonal injury to neighboring glial cells. In this study, we show that mice deficient in neuronal nitric oxide synthase (nNOS −/− ) are more vulnerable than WT mice to toxin-induced peripheral neuropathy. The administration of NO donors to primary dorsal root ganglion cultures prevents axonal degeneration induced by acrylamide in a dose-dependent manner. We demonstrate that NO-induced axonal protection is dependent on hypoxia-inducible factor (HIF)-1-mediated transcription of erythropoietin (EPO) within glial (Schwann) cells present in the cultures. Transduction of Schwann cells with adenovirus AdCA5 encoding a constitutively active form of HIF-1α results in amelioration of acrylamide-induced axonal degeneration in an EPOdependent manner. Mice that are partially deficient in HIF-1α (HIF-1α +/− ) are also more susceptible than WT littermates to toxic neuropathy. Our results indicate that NO→HIF-1→EPO signaling represents an adaptive mechanism that protects against axonal degeneration.

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“…The involvement of HIF-1α in PH was documented by the finding that heterozygous mice when exposed to hypoxia (10% O 2 for 1 to 6 weeks) developed less polycythemia, right ventricular hypertrophy, pulmonary hypertension, pulmonary vascular remodeling, and weight loss than wild-type mice [46]. HIF-2α, which is abundantly expressed in the lung, is also involved in PH, in that heterozygous mice are fully protected against PH and right ventricular hypertrophy caused by chronic hypoxia [47].…”

Section: Hypoxia Signaling In the Lungmentioning

confidence: 99%

Hypoxia and chronic lung disease

et al. 2007

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The lung is both the conduit for oxygen uptake and is also affected by hypoxia and hypoxia signaling. Decreased ventilatory drive, airway obstructive processes, intra-alveolar exudates, septal thickening by edema, inflammation, fibrosis, or damage to alveolar capillaries will all interpose a significant and potentially life-threatening barrier to proper oxygenation, therefore enhancing the alveolar/arterial pO 2 gradient. These processes result in decreased blood and tissue oxygenation. This review addresses the relationship of hypoxia with lung development and with lung diseases. We particularly focus on molecular mechanisms underlying hypoxia-driven physiological and pathophysiological lung processes, specifically in the infant lung, pulmonary hypertension, and chronic obstructive pulmonary disease.Keywords Hypoxia . Lung . Pathology . HIF Air, containing oxygen at approximately 21% partial pressure at sea level (140-150 mmHg), travels through up to 20 generations of airways by mass flow and then diffuses into the gas exchange units (alveoli) in the lung with a partial pressure of approximately 105-110 mmHg. The human lung contains approximately 480 million alveoli, which represent 64% of total lung structure. These alveoli are elegantly packed in only 1.3-2.6 L of total lung volume, providing a surface area of 120-150 m 2 , equivalent to the dimensions of a "tennis court" dedicated for gas exchange. Although the molecular determinants of lung size are not known, oxygen diffusion constant and gas exchange surface area are roughly proportional to body weight and oxygen consumption in different species [1]. Physical hyperactivity and exposure to a cold environment or high altitude lead to increased oxygen diffusion capacity, in proportion to enhanced oxygen consumption [1].Decreased ventilatory drive, airway obstructive processes, intraalveolar exudates, septal thickening by edema, inflammation, fibrosis, or damage to alveolar capillaries will all interpose a significant and potentially life-threatening barrier to proper oxygenation, therefore enhancing the alveolar/ arterial pO 2 gradient. This review addresses the contribution of hypoxia to lung diseases and the potential molecular mechanisms involved in hypoxia-driven physiological and pathophysiological lung processes (Fig. 1), particularly in the infant lung, pulmonary hypertension, and chronic obstructive pulmonary disease. The fundamental concepts underlying hypoxia-induced gene expression and the molecular regulation of HIF(s) also apply to the lung, and they will be cited in relation to their demonstrated role in lung physiology or pathophysiology.

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Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α

Cited by 606 publications

References 49 publications

Functional Activation of Heat Shock Factor and Hypoxia-Inducible Factor in the Kidney

Functional Activation of Heat Shock Factor and Hypoxia-Inducible Factor in the Kidney

Nitric oxide prevents axonal degeneration by inducing HIF-1–dependent expression of erythropoietin

Hypoxia and chronic lung disease

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