Oxygen-dependent expression of hypoxia-inducible factor-1α in renal medullary cells of rats

Zou, Ai-Ping; Yang, Zhi-Zhang; Li, Pin‐Lan; Cowley, Allen W.

doi:10.1152/physiolgenomics.2001.6.3.159

Cited by 52 publications

(63 citation statements)

References 45 publications

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“…After centrifugation of the homogenate at 6,000 g for 5 min at 4°C, the supernatant containing membrane and cytosolic components, termed homogenate, was divided into aliquots, frozen in liquid nitrogen, and stored at Ϫ80°C. Western blot analyses were performed as described previously (54). Briefly, protein samples (20 g) were subjected to 10% SDS-PAGE gel electrophoresis and electrophoretically transferred onto nitrocellulose membranes.…”

Section: Methodsmentioning

confidence: 99%

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Expression and actions of HIF prolyl-4-hydroxylase in the rat kidneys

Sundy²,

Chen³

et al. 2007

American Journal of Physiology-Renal Physiology

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Hypoxia inducible factor (HIF) prolyl-4-hydroxylase domain-containing proteins (PHDs) promote the degradation of HIF-1␣. Because HIF-1␣ is highly expressed in the renal medulla and HIF-1␣-targeted genes such as nitric oxide synthase, cyclooxygenase, and heme oxygenase are important in the regulation of renal medullary function, we hypothesized that PHD regulates HIF-1␣ levels in the renal medulla and, thereby, participates in the control of renal Na ϩ excretion. Using real-time RT-PCR, Western blot, and immunohistochemical analyses, we have demonstrated that all three isoforms of PHD, PHD1, PHD2, and PHD3, are expressed in the kidneys and that PHD2 is the most abundant isoform. Regionally, all PHDs exhibited much higher levels in renal medulla than cortex. A furosemide-induced increase in renal medullary tissue PO2 significantly decreased PHD levels in renal medulla, whereas hypoxia significantly increased mRNA levels of PHDs in cultured renal medullary interstitial cells, indicating that O2 regulates PHDs. Functionally, the PHD inhibitor L-mimosine (L-Mim, 50 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ip for 2 wk) substantially upregulated HIF-1␣ expression in the kidneys, especially in the renal medulla, and remarkably enhanced (by Ͼ80%) the natriuretic response to renal perfusion pressure in Sprague-Dawley rats. Inhibition of HIF transcriptional activity by renal medullary transfection of HIF-1␣ decoy oligodeoxynucleotides attenuated L-Mim-induced enhancement of pressure natriuresis, which confirmed that HIF-1␣ mediated the effect of L-Mim. These results indicate that highly expressed PHDs in the renal medulla make an important contribution to the control of renal Na ϩ excretion through regulation of HIF-1␣ and its targeted genes. fluid homeostasis; anoxia; natriuretic factor; gene transcription; renal tubules; renal hemodynamics IT IS WELL KNOWN that PO 2 is much lower in the renal medulla than in the renal cortex because of relative "underperfusion," the countercurrent O 2 diffusion between descending and ascending vasa recta, and the high metabolic ion transport activity of the thick ascending limb of Henle in the renal medullary region (6, 10). To adapt to this low-PO 2 milieu, the renal medulla has naturally developed various mechanisms to protect the cells from ischemic and hypoxic injury (5,6,15) and to ensure that the cells in this kidney region function normally in a hypoxic environment (6, 10). Increase in tissue blood perfusion to facilitate the O 2 supply and inhibition of tubular metabolic activity to decrease O 2 demands (5,6,15,53) are the common outcomes of various adaptive actions induced by different renal medullary factors such as nitric oxide (NO), prostaglandins, and heme oxygenase (HO) products. Hypoxia inducible factor (HIF)-1␣, the master regulator of adaptation to hypoxia, has been shown to activate gene transcription of many O 2 -sensitive genes such as NO synthase (NOS), cyclooxygenase (COX), HO, and vascular endothelial growth factor (21,25,26,32,38,45,50,53). The participation of the products controlled...

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Section: Methodsmentioning

confidence: 99%

“…We recently reported that HIF-1␣ is abundantly expressed in renal medullary tissue (54). However, it remains unknown how the renal medullary HIF-1␣ levels are regulated in response to low PO 2 .…”

mentioning

confidence: 99%

Expression and actions of HIF prolyl-4-hydroxylase in the rat kidneys

Sundy²,

Chen³

et al. 2007

American Journal of Physiology-Renal Physiology

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“…When this occurs, renal cells initially respond with protective mechanisms that center around the phosphorylation of extracellular signal-regulated protein kinases 1 and 2 and the resulting stabilization of both HIF-1α and HIF-2α. [94][95][96]292,[323][324][325] These protective mechanisms include the up-regulation of pro-angiogenic factors such as isoform 164 of VEGF-A that protect against capillary rarefaction, and increased expression of matrix metalloproteinases that effect repair and protect against fibrosis by degrading extracellular matrix. 326,327 In addition, short-term exposure to hypoxia leads to increased renal expression of antioxidants such as nuclear factor erythroid 2-related factor 2, hemeoxygenase 1, and metallothionein I that protect against fibrosis and inflammation induced by reactive oxygen species.…”

Section: The Hypoxia Death Cyclementioning

confidence: 99%

Hypoxia: The Force that Drives Chronic Kidney Disease

Colgan

Shelley

2016

Clinical Medicine & Research

125

111

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In the United States the prevalence of end-stage renal disease (ESRD) reached epidemic proportions in 2012 with over 600,000 patients being treated. The rates of ESRD among the elderly are disproportionally high. Consequently, as life expectancy increases and the baby-boom generation reaches retirement age, the already heavy burden imposed by ESRD on the US health care system is set to increase dramatically. ESRD represents the terminal stage of chronic kidney disease (CKD). A large body of evidence indicating that CKD is driven by renal tissue hypoxia has led to the development of therapeutic strategies that increase kidney oxygenation and the contention that chronic hypoxia is the final common pathway to end-stage renal failure. Numerous studies have demonstrated that one of the most potent means by which hypoxic conditions within the kidney produce CKD is by inducing a sustained inflammatory attack by infiltrating leukocytes. Indispensable to this attack is the acquisition by leukocytes of an adhesive phenotype. It was thought that this process resulted exclusively from leukocytes responding to cytokines released from ischemic renal endothelium. However, recently it has been demonstrated that leukocytes also become activated independent of the hypoxic response of endothelial cells. It was found that this endothelium-independent mechanism involves leukocytes directly sensing hypoxia and responding by transcriptional induction of the genes that encode the β2-integrin family of adhesion molecules. This induction likely maintains the long-term inflammation by which hypoxia drives the pathogenesis of CKD. Consequently, targeting these transcriptional mechanisms would appear to represent a promising new therapeutic strategy.

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“…Sophisticated counterbalance mechanisms help to restore renal oxygen homeostasis (49), and some researchers have proposed that HIF physiologically takes part in this fine-tuning network (50,51). However, evidence for HIF upregulation in normal kidneys is inconsistent (for review, see reference [6]).…”

Section: Stable Long-term Allografts Are Void Of Hif-1␣mentioning

confidence: 99%

Immunohistochemical Detection of Hypoxia-Inducible Factor-1α in Human Renal Allograft Biopsies

Rosenberger

Pratschke²,

Rudolph³

et al. 2007

Journal of the American Society of Nephrology

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Although it generally is accepted that renal hypoxia may occur in various situations after renal transplantation, direct evidence for such hypoxia is lacking, and possible implications on graft pathophysiology remain obscure. Hypoxiainducible factors (HIF) are regulated at the protein level by oxygen-dependent enzymes and, hence, allow for tissue hypoxia detection. With the use of high-amplification HIF-1␣ immunohistochemistry in renal biopsies, hypoxia is shown at specific time points after transplantation with clinicohistologic correlations. Immediately after engraftment, in primarily functioning grafts, abundant HIF-1␣ is present and correlates with cold ischemic time >15 h and/or graft age >50 yr (P < 0.04). In contrast, a low HIF-1␣ score correlates with primary nonfunction, likely reflecting loss of oxygen consumption for tubular transport. Protocol biopsies at 2 wk show widespread HIF-1␣ induction, irrespective of histology. Beyond 3 mo, both protocol biopsies and indicated biopsies are virtually void of HIF-1␣, with the only exception being clinical/subclinical rejection. HIF-derived transcriptional adaptation to hypoxia may counterbalance, at least partly, the negative impact of cold preservation and warm reflow injury. Transient hypoxia at 2 wk may be induced by hyperfiltration, hypertrophy, calcineurin inhibitor-induced toxicity, or a combination of these. Lack of detectable HIF-1␣ at 3 mo and beyond suggests that at this time point, graft oxygen homeostasis occurs. The strong correlation between hypoxia and clinical/subclinical rejection in long-term grafts suggests that hypoxia is involved in such graft dysfunction, and HIF-1␣ immunohistochemistry could enhance the specific diagnosis of acute rejection. I t generally is accepted that in renal transplants, hypoxia occurs in association with cold storage followed by warm reflow or as part of calcineurin inhibitor (CNI) toxicity (1). However, direct evidence for such allograft hypoxia is lacking.Hypoxia-inducible transcription factors (HIF) allow for hypoxia detection at a single cell resolution (for reviews, see references [2][3][4][5][6]). HIF are heterodimers of a constitutive ␤-subunit and one of at least two alternative ␣-subunits. HIF␣ is regulated by oxygen-dependent proteolysis by socalled HIF prolyl hydroxylases (7,8). These key enzymes of HIF␣ degradation are oxygen dependent and can be considered cellular oxygen sensors, because their activity varies in the range of physiologic/pathologic oxygen tensions (9). HIF regulate transcriptional activity of a host of genes that are involved in metabolism, vascular tone, angiogenesis, cell cycle, iron metabolism, radical scavenging, erythropoiesis, inflammation, etc. (for reviews, see references [6,10]). There is sufficient amount of evidence to support the view that the HIF system is ubiquitous, instantaneously upregulated upon hypoxia, and short-lived upon reoxygenation and that many HIF target genes confer cell/tissue protection.Detection of HIF activation in tissue sections requires immunohistoch...

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Oxygen-dependent expression of hypoxia-inducible factor-1α in renal medullary cells of rats

Cited by 52 publications

References 45 publications

Expression and actions of HIF prolyl-4-hydroxylase in the rat kidneys

Expression and actions of HIF prolyl-4-hydroxylase in the rat kidneys

Hypoxia: The Force that Drives Chronic Kidney Disease

Immunohistochemical Detection of Hypoxia-Inducible Factor-1α in Human Renal Allograft Biopsies

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