Activation of heat-shock transcription factor by graded reductions in renal ATP, in vivo, in the rat.

Why, Scott K. Van; Mann, A. S.; Thulin, Gunilla; Zhu, Xiaohong; Kashgarian, Michael; Siegel, Norman J.

doi:10.1172/jci117492

Cited by 65 publications

(46 citation statements)

References 26 publications

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“…Analysis of the ischemic extracts for the presence of HSF revealed that this complex could be supershifted with the addition of antibodies against HSF-1 or HSF-2 ( Figure 1C, compare lanes 2 and 3 with lane 1). The addition of excess amounts of unlabeled oligonucleotides led to the disappearance of the observed DNA-binding HSF complex, as demonstrated previously (23). Therefore, HSF was clearly activated after 45 min of renal ischemia and was identified as a hetero-oligomeric complex consisting of HSF-1 and HSF-2 isoforms.…”

Section: In Vivo Renal Ischemiasupporting

confidence: 78%

“…HSF was inactive in control LLC-PK 1 cells (Figure 3, A and B, 0 min) (23). When cells were subjected to ATP depletion, HSF was rapidly activated as early as 30 min after the injury, with a progressive increase after 240 min of ATP depletion ( Figure 3A).…”

Section: In Vitro Injuriesmentioning

confidence: 97%

“…Studies were conducted with anesthetized male Sprague-Dawley rats (age, 12 to 14 wk; weight, 225 to 280 g), as described previously (23). Rats were housed in metal cages with access to regular chow and tap water ad libitum.…”

Section: Animal Modelmentioning

confidence: 99%

“…Aliquots of nuclear extracts (4 g) were incubated with labeled oligonucleotides (5 ng) under binding conditions [4% glycerol, 1 mM MgCl 2 , 0.5 mM EDTA, 0.5 mM dithiothreitol, 50 mM NaCl, 10 mM Tris-HCl, pH 7.5, 50 g/ml poly(dI-dC)], in a total volume of 10 l. Incubations were performed at room temperatures for 30 min. Protein-DNA complexes were applied to 4% polyacrylamide gels, subjected to electrophoresis, and analyzed by autoradiography, as described previously (23,26).…”

Section: Electrophoretic Mobility Shift Assaysmentioning

confidence: 99%

“…We previously reported that HSF activation results in a functional heat shock response in the kidney in vivo (23) and in LLC-PK 1 cells in vitro (13). Relatively little is known, however, regarding the function of HIF in LLC-PK 1 cells.…”

Section: Hif-1␣ Function In Llc-pk 1 Cellsmentioning

confidence: 99%

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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: In Vivo Renal Ischemiasupporting

confidence: 78%

Section: In Vitro Injuriesmentioning

confidence: 97%

Section: Animal Modelmentioning

confidence: 99%

Section: Electrophoretic Mobility Shift Assaysmentioning

confidence: 99%

Section: Hif-1␣ Function In Llc-pk 1 Cellsmentioning

confidence: 99%

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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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Nitric oxide regulates mitochondrial respiration and functions of articular chondrocytes

Tomita

Sato

Nishikawa

et al. 2001

Arthritis & Rheumatism

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Objective Biologic effects of nitric oxide (NO) have been shown to increase under hypoxic conditions. Because the oxygen tension in joint cavities of patients with arthritis is fairly low, biologic effects of NO would be expected to be significantly large in these compartments. This study was undertaken to investigate the effects of NO on the energy metabolism and functions of articular chondrocytes under different oxygen tension conditions. Methods Articular chondrocytes from rabbits were cultured under various oxygen concentrations in the presence or absence of NO and NOC18, an NO donor. Cellular respiration was measured using a Clark‐type oxygen electrode. Levels of ATP in the cells were determined according to the luciferin‐luciferase method. Cellular synthesis of proteoglycans was determined by measuring the incorporation of radioactivity (derived from 35S‐labeled SO4) into glycosaminoglycans. Expression of stress‐related proteins was evaluated by Western blotting analysis using specific antibodies. Results Respiration and ATP synthesis of cultured chondrocytes were inhibited by NO, particularly under low oxygen concentrations. The presence of either NO or specific inhibitors of mitochondrial electron transport suppressed the synthesis of proteoglycans without affecting cell viability. When exposed to NO, cellular levels of heat‐shock protein 70 (hsp70) and heme oxygenase 1 (HO‐1) increased markedly. The presence of inhibitors of mitochondrial electron transport also increased cellular levels of hsp70 and HO‐1. Conclusion These results suggest that NO generated in the joint might inhibit energy metabolism and the synthesis of proteoglycans of chondrocytes, thereby modulating pathophysiologic processes occurring in patients with arthritis.

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Heat Shock Factor Network in Kidney Diseases

Musiał

Zwołińska

2020

Heat Shock Proteins

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Activation of heat-shock transcription factor by graded reductions in renal ATP, in vivo, in the rat.

Cited by 65 publications

References 26 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 regulates mitochondrial respiration and functions of articular chondrocytes

Heat Shock Factor Network in Kidney Diseases

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