Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously demonstrated using immunocytochemical, histochemical, and biochemical techniques that ischemia in vivo and ATP depletion in vitro result in dissociation of Na(+)-K(+)-adenosinetriphosphatase (ATPase) from the actin cytoskeleton and redistribution to the apical domain in renal proximal tubule cells. To directly evaluate whether apical Na(+)-K(+)-ATPase retained Na+ pumping activity, a rapidly reversible model of cellular ATP depletion in confluent LLC-PK1 cells grown on semipermeable membranes was utilized. Tight-junction integrity, monitored by electrical resistance, was lost during ATP depletion and reestablished during 2 h of ATP repletion. Total cellular Na(+)-K(+)-ATPase activity and total surface membrane [3H]ouabain binding remained constant, but specific apical [3H]ouabain binding increased (7 vs. 26 fmol/filter, P < 0.01). Apical [3H]ouabain binding returned to baseline during 5 h of ATP repletion. Apically applied ouabain was then used to selectively inhibit apical Na(+)-K(+)-ATPase. It had no effect on apical-to-basolateral Na+ flux under physiological conditions (1.3 +/- 0.61 vs. 1.27 +/- 0.46 meq.filter-1.30 min-1), but it increased the apical-to-basolateral flux in ATP-depleted and then repleted monolayers (0.39 +/- 0.12 vs. 0.83 +/- 0.27 meq.filter-1.30 min-1, P < 0.01), implying that apical Na(+)-K(+)-ATPase retained Na+ pumping activity. Together, these data imply that ATP depletion induces loss of surface membrane polarity resulting in redistribution of functional proteins to the alternate domain.
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PMID:Na(+)-K(+)-ATPase that redistributes to apical membrane during ATP depletion remains functional. 823 49

This study was carried out to determine the effect of renal ischaemia on transport systems for organic compounds in the rabbit kidney proximal tubule. Ischaemia for 30 or 60 min. induced glucosuria and phosphaturia, which was accompanied by polyuria and natriuresis. The Na(+)-dependent uptake of glucose, succinate and L-glutamate by brush-border membrane vesicles was not altered by 30 or 60 min. of ischaemia, while the H+/tetraethylammonium antiport was significantly inhibited after 30 min. of ischaemia. When the duration of ischaemia was extended to 120 min. the uptake of glucose and succinate by brush-border membrane vesicles was also significantly attenuated, but the L-glutamate uptake was not altered. The uptake of glucose, succinate and L-glutamate by basolateral membrane vesicles was not impaired even with 120 min. of ischaemia, suggesting that transport systems for organic compounds in the brush-border membrane are more sensitive to ischaemia than those in the basolateral membrane. Ouabain-sensitive oxygen consumption in renal cortical slices was not depressed by 60 min. of ischaemia. When kidneys were reperfused for 60 min. following 60 min. of ischaemia, the Na(+)-glucose and Na(+)-succinate cotransport and the H+/tetraethylammonium antiport were not different from the control, but the recovery of alkaline phosphatase was significantly reduced. When kidneys were subjected to ischaemia for 60 min., a loss of brush-border microvilli and plasma membrane was observed after 5 or 60 min. of reflow in the proximal convoluted tubule. After 3 hr of reflow, focal necrosis appeared although the microvilli were partially regenerated.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of renal ischaemia on organic compound transport in rabbit kidney proximal tubule. 858 2

The actin cytoskeleton of proximal tubule cells is important for both the maintenance of membrane domains and attachment to neighboring cells and underlying substrata. Adenosine triphosphate (ATP) depletion during ischemic injury causes early alterations in the actin cytoskeleton, resulting in loss of membrane domains and cellular attachment. We examined the actin cytoskeleton during recovery from ischemic injury. As shown previously in cell culture studies, ATP depletion to 14% of control values from in vivo ischemia resulted in decreases in G-actin consistent with net polymerization of the cytoskeleton. After 20 minutes of recovery restored ATP levels to 24% of control values, percent G-actin increased back to control values, yet cytoplasmic actin polymerized with little evidence of apical recovery. After 120 minutes of recovery, ATP levels had increased to 48% of control values with little qualitative or quantitative change in actin polymerization from 20 minutes of recovery. When ATP levels recovered to 65% of control values at 360 minutes after ischemia, movement of F-actin back toward the apical surface was observed. These data, along with prior data using maleic acid, suggest that thresholds of cellular ATP may cause differing effects on distinct cellular actin pools. We conclude that actin cytoskeletal recovery occurs very early and may be necessary for reestablishment of polarity essential for normal reabsorptive functions.
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PMID:Early recovery of the actin cytoskeleton during renal ischemic injury in vivo. 862 32

ATP-sensitive K+ channels (KATP channels) form a link between the metabolic state of the cell and the permeability of the cell membrane for K+ which, in turn, is a major determinant of cell membrane potential. KATP channels are found in many different cell types. Their regulation by ATP and other nucleotides and their modulation by other cellular factors such as pH and kinase activity varies widely and is fine-tuned for the function that these channels have to fulfill. In most excitable tissues they are closed and open when cell metabolism is impaired; thereby the cell is clamped in the resting state which saves ATP and helps to preserve the structural integrity of the cell. There are, however, notable exceptions from this rule; in pancreatic beta-cells, certain neurons and some vascular beds, these channels are open during the normal functioning of the cell. In the renal tubular system, KATP channels are found in the proximal tubule, the thick ascending limb of Henle's loop and the cortical collecting duct. Under physiological conditions, these channels have a high open probability and play an important role in the reabsorption of electrolytes and solutes as well as in K+ homeostasis. The physiological role of their nucleotide sensitivity is not entirely clear; one consequence is the coupling of channel activity to the activity of the Na-K-ATPase (pump-leak coupling), resulting in coordinated vectorial transport. In ischemia, however, the reduced ATP/ADP ratio would increase the open probability of the KATP channels independently from pump activity; this is particularly dangerous in the proximal tubule, where 60 to 70% of the glomerular ultrafiltrate is reabsorbed. The pharmacology of KATP channels is well developed including the sulphonylureas as standard blockers and the structurally heterogeneous family of channel openers. Blockers and openers, exemplified by glibenclamide and levcromakalim, show a wide spectrum of affinities towards the different types of KATP channels. Recent cloning efforts have solved the mystery about the structure of the channel: the KATP channels in the pancreatic beta-cell and in the principal cell of the renal cortical collecting duct are heteromultimers, composed of an inwardly rectifying K+ channel and sulphonylurea binding subunit(s) with unknown stoichiometry. The proteins making up the KATP channel in these two cell types are different (though homologous), explaining the physiological and pharmacological differences between these channel subtypes.
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PMID:ATP-sensitive K+ channels in the kidney. 887 50

The uptake of organic anion, p-aminohippurate (PAH), and organic cation, tetraethylammonium (TEA), was measured in cortical slices and plasma membrane vesicles isolated from the proximal tubule of ischemic rabbit kidneys. The uptake of PAH or TEA in cortical slices increased after 30 or 60 min of ischemia. When the kidneys were reperfused for 30 min, the uptake of organic ions returned to control levels. When ischemic (60 min) slices were preincubated for 120 min in an oxygenated medium, the stimulatory effect of ischemia on organic ion uptake was not observed. The PAH uptake by basolateral membrane vesicles and brush border membrane vesicles (BBMV) was not altered following 60 min of ischemia. However, the TEA uptake by BBMV but not basolateral membrane vesicles was significantly reduced. The dissipation rate of H+ gradient across the BBMV was similar in control and ischemic kidneys. The Vmax for TEA transport in BBMV isolated from ischemic kidneys was significantly reduced, but the Km was not altered. These results indicate that the organic cation secretory system is more vulnerable to ischemia than the organic anion secretory system in the rabbit renal proximal tubule.
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PMID:Effect of renal ischemia on organic anion and cation transport in rabbit proximal tubule. 899 45

Ischemic renal injury is associated with changes in the expression of a number of genes. Although pH regulation is undoubtedly important during the recovery from ischemia, the expression of acid-base transporters during acute ischemic renal failure has not been studied. In the present study, levels of mRNA encoding the colonic H+-K+-ATPase and four isoforms of the Na+/H+ exchanger (NHE-1, NHE-2, NHE-3 and NHE-4) were measured by quantitative Northern analysis in rat renal cortex and medulla following ischemia-reperfusion injury. Rats were subjected to 30 minutes of renal artery occlusion and then sacrificed either 12 or 24 hours after the occlusion was released. The most striking changes followed 30 minutes of occlusion and 12 hours of reperfusion and involved the mRNA for NHE-3 (involved in HCO3- reabsorption in proximal tubule and thick limb) and colonic H+-K+-ATPase (involved in HCO3- reabsorption in collecting duct). These changes were: (1) a approximately 75% decrease in NHE-3 mRNA in both cortex and medulla; and (2) an approximately 8-fold increase in colonic H+-K+-ATPase mRNA in the cortex. At 12 hours of reperfusion, there was a 66% reduction in the Na+/H+ exchanger (NHE-3) activity as assayed by acid-stimulated 22Na+ influx into brush border membrane vesicles (P < 0.01). After 24 hours of reperfusion, NHE-3 mRNA remained suppressed while cortical colonic H+-K+-ATPase mRNA declined to only twice the control level. Medullary colonic H+-K+-ATPase mRNA did not change significantly. Gastric H+-K+-ATPase mRNA in cortex or medulla remained the same at 0, 12, and 24 hours after reperfusion. Cortical NHE-1 increased mildly at 12 and 24 hours of reperfusion whereas a moderate decrease in NHE-2 and NHE-4 mRNAs was observed in cortex and medulla after both 12 and 24 hours of reperfusion. We suggest that overexpression of colonic H+-K+-ATPase in the early phase of renal reperfusion injury may be responsible for compensatory reabsorption of increased HCO3- load resulting from suppression of NHE-3. This was supported by a fourfold increase in colonic H+-K+-ATPase mRNA in rats treated with acetazolamide, which causes renal HCO3-wasting. Rapid decline in colonic H+-K+-ATPase expression at 24 hours after reperfusion is likely due to reduced HCO3- delivery to distal tubules resulting from decreased GFR. Overexpression of H+-K+-ATPase may be vital to acid-base homeostasis in the early phase of acute ischemic renal failure.
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PMID:Ischemic-reperfusion injury in the kidney: overexpression of colonic H+-K+-ATPase and suppression of NHE-3. 908 76

Recovery from ischemic renal injury is accompanied by enhanced DNA synthesis and a typical immediate early (IE) gene response. These two processes occur in distinct cell populations, suggesting that the IE gene response does not serve a proliferative function directly. As cellular stress induces an IE response through activation of the stress-activated protein kinases (SAPK) that is not proliferative and can be inhibited by N-acetyl-L-cysteine (NAC), we determined whether the Jun NH2-terminal kinases (JNK), members of the SAPKs, are activated during ischemia and whether NAC administration reduces the IE response and/or the induction of JNK activity. NAC (6 mM/kg body wt) infused 1 h prior to and 1 h following renal ischemia reduced c-fos and c-jun expression by 50 and 70%, respectively. Ischemia increased JNK activity, and this increase was inhibited by NAC. NAC infused animals had a higher glomerular filtration rate at 1 day (NAC, 0.9 +/- 0.2, vs. control, 0.05 +/- 0.01 ml/min, P < 0.001) and 7 days (NAC, 2.0 +/- 0.1, vs. control, 1.2 +/- 0.1, P < 0.001) after the induction of ischemia. NAC did not reduce the extent of proximal tubule necrosis at 24 h after reperfusion but improved histological appearance of the kidney at 7 days. The mechanism by which NAC ameliorates the loss of renal function is unknown but may involve its general properties as an antioxidant or a possible interaction with NAC and NO. We conclude that the IE gene response of the kidney to ischemia reperfusion is a consequence of the stress-activated kinase pathway and that part of the response is deleterious to kidney function and cellular integrity.
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PMID:N-acetyl cysteine ameliorates ischemic renal failure. 908 70

Differential display-polymerase chain reaction (DD-PCR) was used to identify genes that are expressed in kidney following induction of acute ischemic renal injury. The receptor for activated C kinase (RACK1) mRNA expression in kidneys obtained from rats 12 h following ischemia is enhanced twofold compared with sham-operated rats. The maximal enhancement of expression (3.3-fold) is at 7 days following reperfusion. Expression remains elevated at 14 days. RACK1 transcripts and protein are localized to the damaged and regenerating segments of proximal tubules. At 1 day following injury, RACK1 protein is present in the epithelial cells of the damaged S3 segment and in cells sloughed into the tubular lumen. By 5 days following injury, RACK1 protein expression is enhanced in the regenerating cells relining the injured tubules of the S3 segment and in papillary proliferations within regenerating tubules. Increased expression of RACK1 could enhance the activity of PKC and, in so doing, regulate the process of regeneration of the proximal tubule following ischemic renal injury.
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PMID:Ischemia-induced receptor for activated C kinase (RACK1) expression in rat kidneys. 912 91

The renal osmotic stress-induced cotransporter (ROSIT), a new putative member of a family of organic solute transporters, is highly expressed in the kidney. Our in situ hybridization data now reveal that large amounts of ROSIT mRNA can be found in the S3 segment of the proximal tubule. In the developing kidney, ROSIT mRNA is expressed after the S-shaped body stage. Because the S3 segment is the major site of damage in the post-ischemic kidney, we evaluated alterations in ROSIT mRNA expression after ischemic acute tubular necrosis. Renal osmotic stress-induced cotransporter mRNA levels were already decreased eight hours post-ischemia. At seven days post-ischemia, ROSIT mRNA reappeared in a mosaic pattern in the regenerating S3 segment, being fully expressed three weeks after the insult except for focal areas. The exact localization of this putative osmolyte transporter in the kidney, together with that of other known osmolyte transporter will contribute to a better understanding of the mechanism of medullary osmolyte accumulation and its vectorial transport.
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PMID:Renal osmotic stress-induced cotransporter: expression in the newborn, adult and post-ischemic rat kidney. 940 4

After ischemia and reperfusion, severe alterations in the cytoskeletal organization of renal tubular epithelial cells have been reported. These effects, accompanied by a modification in the polarized distribution of some membrane transport proteins, are especially evident in the proximal tubule. In normal proximal tubule cells, actin is concentrated in apical brush border microvilli, along with the actin-binding protein villin. Because villin plays an important role in actin bundling and in microvillar assembly but can also act as an actin-fragmenting protein at higher calcium concentrations, we examined the effects of ischemic injury and reperfusion on the distribution of villin and actin in proximal tubule cells of rat kidney. Using specific antibodies against villin and actin, we show that these proteins redistribute in parallel from the apical to the basolateral plasma membrane within 1 h of reperfusion after ischemia. Ischemia alone had no effect on the staining pattern. Repolarization of villin to the apical membrane begins within hours after reperfusion with enhanced apical localization over time during the period of regeneration. This apical repolarization of villin is accompanied by the migration of actin back to the apical membrane. These results show not only that villin may be involved in the initial disruption of the actin cytoskeleton during reperfusion injury but also that its migration back to the apical domain of these cells accompanies the reestablishment of a normal actin distribution in the brush border.
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PMID:Redistribution of villin to proximal tubule basolateral membranes after ischemia and reperfusion. 943 90


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