UMLS:C0920646 - FACTA Search

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Query: UMLS:C0920646 (renal ischemia)
2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renal ischemia results in both a profound fall in cellular ATP and a rapid induction of the 70 kD heat-shock protein family, HSP-70. The present studies examined the relationship between cellular ATP and induction of the stress response in renal cortex. Cellular ATP, continuously monitored by in vivo 31P-NMR spectroscopy, was reduced and maintained at specific, stable levels in renal cortex by partial aortic occlusion for 45 min. Activation of heat-shock transcription factor (HSF) was detected by gel retardation assay and transcription was confirmed by Northern analysis. Activation of HSF was not present, and HSP-70 mRNA induction did not occur when ATP levels were maintained above 60% preocclusion (control) levels. Reduction in cortical ATP levels to 35-50% preocclusion values resulted in HSF activation and low-level expression of inducible HSP-70 mRNA. Cellular ATP of 20-25% control values resulted in a greater level of HSF activation and subsequent HSP-70 mRNA elaboration. HSF was activated at the end of 15 min of total occlusion. The studies indicate that a 50% reduction in cellular ATP in the renal cortex must occur before the stress response is detectable, that reduction of ATP below 25% control levels produces a more vigorous response, and that reperfusion is not required for initiation of a heat-shock response in the kidney. Cellular ATP, or the metabolic consequences associated with ATP depletion, may be a threshold factor for initiation of a stress response in the kidney.
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PMID:Activation of heat-shock transcription factor by graded reductions in renal ATP, in vivo, in the rat. 792 28

The mechanisms responsible for the loss of cell potassium during renal ischemia are poorly understood. The present studies examined the hypothesis that potassium channels are activated as an early response to hypoxia and contribute to potassium loss independent from an inhibition of active K+ uptake. Potassium flux in suspensions of freshly isolated rat proximal tubules was measured using an ion-selective electrode. Exposure of the tubules to hypoxia for only 2.5 min resulted in a rise in the passive leak rate of K+ but no decrease in active K+ uptake. The passive leak of K+ was associated with a 40% decrease in cell ATP content. The passive K+ efflux was inhibited by 5 mM Ba2+ (95%) and by 15 mM tetraethylammonium (85%) suggesting that K+ channels were the primary route of K+ movement. The effects of K+ channel blockade on the development of hypoxic injury were also examined. Tetraethylammonium and glibenclamide, an inhibitor of ATP-sensitive K+ channels, reduced hypoxic injury as assessed by the release of lactate dehydrogenase or measurement of DNA damage. These results suggest that activation of K+ channels is an early response to hypoxia and contributes to hypoxic renal injury.
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PMID:Activation of potassium channels contributes to hypoxic injury in proximal tubules. 798 84

Previous studies from our laboratory have demonstrated that postischemic infusion of thyroxin (T4) will augment the restoration of cellular ATP and enhance the recovery of renal function. It has not been clear, however, whether T4 has a direct effect on mitochondrial ATP synthesis or an indirect effect by stabilization of the plasma membrane. To differentiate these putative effects, rats were subjected to 45 min of renal ischemia and given either normal saline (0.5 mL) or T4 (20 micrograms/100 g body weight) during the first 15 min of reflow. Cellular ATP levels were assessed by 31P-nuclear magnetic resonance spectroscopy, and release of lactate dehydrogenase (LDH) was used as an index of plasma membrane integrity at 30 and 120 min of reflow. In rats given normal saline, renal ATP had returned to only 57.9 +/- 1.4% of preischemic values at 30 min of reflow and 66.1 +/- 1.4% by 120 min. LDH release was 13 +/- 0.89% at 30 min and 14.6 +/- 1.6% at 120 min. In contrast, T4-treated animals had ATP levels of 70.2 +/- 2.0% at 30 min and 84.0 +/- 1.9% at 120 min, whereas LDH release was elevated to values similar to those in normal saline-treated rats, 14.9 +/- 1.5% and 14.4 +/- 0.5% at 30 min and 120 min, respectively (nonischemic LDH 8.8 +/- 0.8%). These data suggest that T4 stimulates the recovery of renal ATP by a direct effect on synthesis rather than an indirect effect related to global improvement in cellular integrity.
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PMID:Disassociation of postischemic recovery of renal adenosine triphosphate and cellular integrity. 837 18

Iron-dependent free radical reactions and renal ischemia are believed to be critical mediators of myohemoglobinuric acute renal failure. Thus, this study assessed whether catalytic iron exacerbates O2 deprivation-induced proximal tubular injury, thereby providing an insight into this form of renal failure. Isolated rat proximal tubular segments (PTS) were subjected to either hypoxia/reoxygenation (H/R: 27:15 min), "chemical anoxia" (antimycin A; 7.5 microM x 45 min), or continuous oxygenated incubation +/- ferrous (Fe2+) or ferric (Fe3+) iron addition. Cell injury (% lactic dehydrogenase [LDH] release), lipid peroxidation (malondialdehyde, [MDA]), and ATP depletion were assessed. Under oxygenated conditions, Fe2+ and Fe3+ each raised MDA (approximately 7-10x) and decreased ATP (approximately 25%). Fe2+, but not Fe3+, caused LDH release (31 +/- 2%). During hypoxia, Fe2+ and Fe3+ worsened ATP depletion; however, each decreased LDH release (approximately 31 to approximately 22%; P < 0.01). Fe(2+)-mediated protection was negated during reoxygenation because Fe2+ exerted its intrinsic cytotoxic effect (LDH release: Fe2+ alone, 31 +/- 2%; H/R 36 +/- 2%; H/R + Fe2+, 41 +/- 2%). However, Fe(3+)-mediated protection persisted throughout reoxygenation because it induced no direct cytotoxicity (H/R, 39 +/- 2%; H/R + Fe3+, 25 +/- 2%; P < 0.002). Fe3+ also decreased antimycin toxicity (41 +/- 4 vs. 25 +/- 3%; P < 0.001) despite inducing marked lipid peroxidation and without affecting ATP. These results indicate that catalytic iron can mitigate, rather than exacerbate, O2 deprivation/reoxygenation PTS injury.
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PMID:Inorganic iron effects on in vitro hypoxic proximal renal tubular cell injury. 843 70

The transcription factors controlling the complex genetic response to ischemia and their modes of regulation are poorly understood. We found that ATF-2 and c-Jun DNA binding activity is markedly enhanced in post-ischemic kidney or in LLC-PK1 renal tubular epithelial cells exposed to reversible ATP depletion. After 40 min of renal ischemia followed by reperfusion for as little as 5 min, binding of ATF-2 and c-Jun, but not ATF-3 or CREB (cAMP response element binding protein), to oligonucleotides containing either an ATF/cAMP response element (ATF/CRE) or the jun2TRE from the c-jun promoter, was significantly increased. Binding to jun2TRE and ATF/CRE oligonucleotides occurred with an identical time course. In contrast, nuclear protein binding to an oligonucleotide containing a canonical AP-1 element was not detected until 40 min of reperfusion, and although c-Jun was present in the complex, ATF-2 was not. Incubating nuclear extracts from reperfused kidney with protein phosphatase 2A markedly reduced binding to both the ATF/CRE and jun2TRE oligonucleotides, compatible with regulation by an ATF-2 kinase. An ATF-2 kinase, which phosphorylated both the transactivation and DNA binding domains of ATF-2, was activated by reversible ATP depletion. This kinase coeluted on Mono Q column chromatography with a c-Jun amino-terminal kinase and with the peak of stress-activated protein kinase, but not p38, immunoreactivity. In conclusion, DNA binding activity of ATF-2 directed at both ATF/CRE and jun2TRE motifs is modulated in response to the extreme cellular stress of ischemia and reperfusion or reversible ATP depletion. Phosphorylation-dependent activation of the DNA binding activity of ATF-2, which appears to be regulated by the stress-activated protein kinases, may play an important role in the earliest stages of the genetic response to ischemia/reperfusion by targeting ATF-2 and c-Jun to specific promoters, including the c-jun promoter and those containing ATF/CREs.
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PMID:Ischemia and reperfusion enhance ATF-2 and c-Jun binding to cAMP response elements and to an AP-1 binding site from the c-jun promoter. 853 Apr 13

ATP-depletion in renal cultured cells has been used as a model for studying various cytoskeletal and functional alterations induced by renal ischemia. This communication explores the reversibility of these effects utilizing a novel method [1] that depleted ATP (ATP-D) to 2% of control within 30 minutes and caused complete recovery (REC) of ATP in one hour. Under confocal microscopy, ATP-D (30 min) caused thinning of F-actin from the microvilli, cortical region, and basal stress fibers, with the concurrent appearance of intracellular F-actin patches. These changes were more pronounced after 60 minutes of ATP-D. One hour of REC following 30 minutes of ATP-D produced complete recovery of F-actin in each region of the cell. However, after 60 minutes of ATP-D, a heterogeneous F-actin recovery pattern was observed: almost complete recovery of the apical ring and microvilli, thinned cortical actin with occasional breaks along the basolateral membrane, and a dramatic reduction in basal stress fiber density. The time course of cortical actin and actin ring disruption and recovery coincided with a drop recovery in the transepithelial resistance and the cytoskeletal dissociation and reassociation of the Na,K-ATPase. Additionally, the microvilli retracted into the cells during ATP-D, a process that was reversed during REC. Triton extraction and confocal microscopy demonstrated that villin remained closely associated with microvillar actin during both ATP-D and REC. These distinctive regional differences in the responses of F-actin to ATP depletion and repletion in cultured renal epithelial cells may help to clarify some of the differential tubular responses to ischemia and reperfusion in the kidney.
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PMID:Actin and villin compartmentation during ATP depletion and recovery in renal cultured cells. 858 43

The effects of ischemia on the maturation of secretory proteins are not well understood. Among several events that occur during ischemia-reperfusion are a rapid and extensive decrease in ATP levels and an alteration of cellular oxidative state. Since the normal folding and assembly of secretory proteins are mediated by endoplasmic reticulum (ER) molecular chaperones, the function of which depends on ATP and maintenance of an appropriate redox environment, ischemia might be expected to perturb folding of secretory proteins. In this study, whole animal and cultured cell models for the epithelial ischemic state were used to examine this possibility. After acute kidney ischemia, marked increases in the mRNA levels of the ER chaperones glucose-regulated protein (grp)78/immunoglobulin-binding protein (BiP), grp94, and ER protein (ERp)72 were noted. Likewise, when cellular ATP was depleted to less than 10% of control with antimycin A, mRNA levels of BiP, ERp72, and grp94 were increased in kidney and thyroid epithelial cell culture models. Since the signal for the up-regulation of these stress proteins is believed to be the accumulation of misfolded/misassembled secretory proteins in the ER, their induction after ischemia in vivo and antimycin treatment of cultured cells suggests that maturation of secretory proteins in the ER lumen might indeed be perturbed. To analyze the effects of antimycin A on the maturation of secretory proteins, we studied the fate of thyroglobulin (Tg), a large oligomeric secretory glycoprotein, the folding and assembly of which seems to require a variety of ER chaperones. Treatment of cultured thyroid epithelial cells with antimycin A greatly inhibited ( > 90%) the secretion of Tg. Sucrose density gradient analysis revealed that in antimycin A-treated cells Tg associates into large macromolecular complexes which, by immunofluorescence, appeared to localize to the ER. Furthermore, coimmunoprecipitation studies after antimycin A treatment demonstrated that Tg stably associates with BiP, grp94, and ERp72. Together, our results suggest that a key cellular lesion in ischemia is the misfolding of secretory proteins as they transit the ER, and this leads not only to increased expression of ER chaperones but also to their stable association with and the subsequent retention of at least some misfolded secretory proteins.
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PMID:Perturbations in maturation of secretory proteins and their association with endoplasmic reticulum chaperones in a cell culture model for epithelial ischemia. 871 Sep 14

The 72-kDa heat stress protein (HSP-72) is an inducible cytoprotectant protein. Although transient renal ischemia in vivo induces HSP-72, it is not known whether prior heat stress protects renal epithelial cells from injury mediated by ATP depletion. To evaluate this hypothesis, opossum kidney (OK) cells were exposed to sodium cyanide and 2-deoxy-D-glucose in the absence of medium glucose, a maneuver that reduced cell ATP content to < 10% of the control value within 10 min and decreased cell survival. One day after 2 h of ATP depletion, OK cells previously exposed to heat stress (to induce accumulation of HSP-72) exhibited marked improvement in survival (a > 4-fold increase in total DNA), less uptake of vital dye, and less release of lactate dehydrogenase (LDH) than cells subjected to ATP depletion alone (23.0 +/- 1.6 vs. 34.1 +/- 1.2% of total LDH, respectively). Enhanced clonogenicity post-heat stress was completely prevented by cycloheximide and positively correlated with the steady-state content of HSP-72. In the recovery period after ATP depletion, cell ATP content, maximum mitochondrial ATP production rate, and total LDH activity were all significantly higher in cells with abundant HSP-72. Although the protective effects associated with heat stress are likely to be multifactoral, preserved cell metabolism and higher ATP content could enhance cellular repair processes after ATP depletion.
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PMID:Prior heat stress enhances survival of renal epithelial cells after ATP depletion. 876 25

Circulatory assist devices are used to treat patients awaiting cardiac transplantation to preserve life as well as to permit recovery of end-organ function. The efficacy of pulseless perfusion versus pulsatile perfusion in the recovery of end-organ function has not been fully determined. In this study, the efficacy of pulseless perfusion compared to pulsatile perfusion on the recovery of renal function after a 30 min period of normothermic ischemia was examined. Pigs were randomly assigned to four groups. In all groups, acute renal ischemia was induced by clamping both renal arteries for 30 min. Reperfusion for 120 min was performed using either pulsatile perfusion or pulseless perfusion at 65 +/- 1.6 mm Hg (Groups I [pulsatile] and II [pulseless]) and at 40 +/- 1.1 mm Hg (Groups III [pulsatile] and IV [pulseless]). After reperfusion, renal blood flow, hemodynamic power (pressure * flow: hemodynamic power), oxygen consumption (VO2), tissue ATP, and urine output (UO) in Groups I, II, and III were significantly higher than in Group IV (p < .01 by ANOVA). Histopathologic examinations were not significantly different between groups. Under hypotensive conditions, pulsatile perfusion improves hemodynamic power delivery to the organ compared to pulseless perfusion. These results suggest that a pulseless pump is acceptable as an assist device when normal flow or perfusion pressure is maintained.
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PMID:Effect of pulsatility and hemodynamic power on recovery of renal function. 894 75

Renal ischemia induces cytoskeletal alterations, membrane perturbations, including bleb formation, and ultimately membrane lysis. The mechanisms that underlie these alterations are largely unknown. Through the use of isolated rat renal proximal tubule fragments and calibrated micropipette techniques, two potential mechanisms for membrane bleb formation during ATP depletion were examined: 1) decreased cytoskeletal retention of the plasma membrane and 2) increased intracellular pressure. Under control conditions, the pressure required to pull the membrane from the underlying cellular matrix was 73 +/- 10 kdyn/cm2. After 30 min of ATP depletion, this pressure was diminished by >95% and blebs began to emerge from the basal membrane. The intracellular pressure within these blebbed cells was only 0.08 +/- 0.02 kdyn/cm2. These observations indicate that, during ATP depletion, the strength of membrane retention diminished until the relatively low intracellular pressure was capable of driving membrane bleb formation. Cytochalasin D, which disrupts the actin cytoskeleton, decreased the strength of membrane retention by 65 +/- 7%. This suggests that, during ATP depletion, alterations of the actin cytoskeleton may mediate the loss of membrane retention.
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PMID:Loss of plasma membrane structural support in ATP-depleted renal epithelia. 912 86

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