Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0920646 (renal ischemia)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Xanthine oxidase (XO) activity and hydroxyl radical (.OH) formation are widely proposed mediators of renal reperfusion injury, potentially altering the severity of, and recovery from, postischemic acute renal failure. The goal of this study was to ascertain whether combination XO inhibitor (oxypurinol) and .OH scavenger (Na benzoate) therapy, given at the time of renal ischemia, alters the extent of: (1) tubular necrosis and filtration failure; (2) DNA fragmentation/apoptosis (assessed in situ by terminal deoxynucleotidyl transferase reactivity); (3) early tubular regenerative responses (proliferating cell nuclear antigen expression; (3H)thymidine incorporation); and (4) the rate and/or degree of functional and morphologic repair. The effects of XO inhibition, .OH scavengers, and "catalytic" iron (FeSO4) on human proximal tubular cell proliferation in vitro were also assessed with a newly established cell line (HK-2). Male Sprague-Dawley rats were subjected to 35 min of bilateral renal arterial occlusion with or without oxypurinol/benzoate therapy. These agents did not alter the extent of tubular necrosis or filtration failure, proliferating cell nuclear antigen expression or thymidine incorporation, or the rate/extent of renal functional/morphologic repair. DNA fragmentation did not precede tubular necrosis, and it was unaffected by antioxidant therapy. By 5 days postischemia, both treatment groups demonstrated regenerating epithelial fronds that protruded into the lumina. These structures contained terminal deoxynucleotidyl transferase-reactive, but morphologically intact, cells, suggesting the presence of apoptosis. Oxypurinol and .OH scavengers (benzoate; dimethylthiourea) suppressed in vitro tubular cell proliferation; conversely, catalytic Fe had a growth-stimulatory effect. These results suggest that: (1) XO inhibition/.OH scavenger therapy has no discernible net effect on postischemic acute renal failure; (2) DNA fragmentation does not precede tubular necrosis, suggesting that it is not a primary mediator of ischemic cell death; and (3) antioxidants can be antiproliferative for human tubular cells, possibly mitigating their potential beneficial effects.
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PMID:An evaluation of antioxidant effects on recovery from postischemic acute renal failure. 791 60

Chronic activation of the circulating renin-angiotensin-aldosterone system (RAAS), as can occur with unilateral renal ischemia (URI), is associated with an adverse structural remodeling of the right and left ventricles characterized by reparative (i.e., microscopic scars) and reactive (i.e., perivascular/interstitial) fibrosis. The time course and cells involved in fibroplastic and fibrogenic phases of these events are unclear. Hearts were examined over the course of 8 weeks in rats infused with either angiotensin II or aldosterone, and compared to rats with URI. Tissue sections from the same heart were stained with hematoxylin and eosin, collagen specific picrosirius red, or immunolabeled with PCNA or alpha smooth muscle actin antibody. With angiotensin II or renal ischemia, fibroblast proliferation, presenting as focal accumulations at both sites of myocyte necrosis and widespread perivascular locations, was present in each ventricle on days 2 and 4, but not thereafter, alpha-Smooth muscle actin containing cells (myofibroblasts) appeared at day 2 and persisted through week 2 with renal ischemia and week 6 with angiotensin II. Macrophages, neutrophils and lymphocytes were transiently found at sites of necrosis between day 2-4 of renal ischemia. AngII-induced necrotic sites were characterized by macrophages and lymphocytes from day 2 through week 6, and neutrophils at day 2-4. Increased collagen volume fraction, presenting as immature scars associated with fibroblast clusters and interstitial/perivascular fibrosis, was evident on day 14 in both ventricles. In contrast, fibroblast proliferation during aldosterone infusion did not appear in both ventricles until week 3 and was associated with a subsequent reparative and reactive fibrosis as early as 4 weeks. Myofibroblasts became evident between 3-6 weeks; macrophages and lymphocytes were seen between 3-8 weeks. Neutrophils were not seen at any time point with aldosterone. Thus, the temporal cellular response and appearance of myocardial fibrosis associated with chronic elevations in angiotensin II and/or aldosterone differ. We conclude that separate pathogenic mechanisms are operative with these effector hormones of the RAAS.
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PMID:Temporal differences in fibroblast proliferation and phenotype expression in response to chronic administration of angiotensin II or aldosterone. 852 18

Contralateral uninephrectomy attenuates unilateral ischemic renal injury functionally and morphologically. In this study we investigated the effects of uninephrectomy on apoptotic renal cell death and tubular regeneration in ischemic acute renal failure (ARF) in rats. Unilateral ischemic injury was provoked by a 60-min left renal artery occlusion in right-nephrectomized (Nx) and sham-nephrectomized (sham-Nx) rats. Uninephrectomy attenuated tubular damage 48 h following the renal ischemia Apoptotic cells were found in renal tissue as early as 3 h after reperfusion and increased in number by 12 h. The "ladder" pattern of DNA fragments on agarose gel electrophoresis was also apparent in ischemic kidney. Uninephrectomy reduced apoptotic cells and DNA fragmentation. The expression of proliferating cell nuclear antigen (PCNA) could be seen 24 h after reperfusion and progressively increased thereafter PCNA expression in ischemic kidney was greater in Nx than sham-Nx rats at 24 h after renal reperfusion. These data suggest that uninephrectomy reduces apoptotic cells and DNA fragmentation and enhances PCNA expression. The reduced apoptotic cell death and enhanced cell regeneration may be importantly involved in the uninephrectomy-induced attenuation of ischemic acute renal failure in rats.
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PMID:Uninephrectomy reduces apoptotic cell death and enhances renal tubular cell regeneration in ischemic ARF in rats. 889 14

To clarify the development of tubular necrosis and its healing process in ischemic renal failure observing degeneration, necrosis, cell proliferation and the involvement of apoptosis in the renal tubular epithelial cells before and after renal ischemia in rats through morphological examination. Eight week-old male rats were used for this study. The model for acute renal failure was by obstruction of bilateral renal arteries and veins for 45 minutes in several intervals (0 hr, 1 hr, 3 hr, 6 hr, 12 hr, 24hr, 48 hr, 96 hr, 1 week, 2 weeks and 4 weeks) each following reperfusion. Urinary beta 2-microglobulin (BMG) levels were measured to evaluate renal tubular function. In evaluating tubular necrosis and cell proliferation, observations of renal tubular tissue were made serially by use of light microscopy and immunological staining of proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine (BrdU), respectively. The number of nuclei in the proximal tubular epithelium/circumference of the basement membrane (n/BM index) was calculated using a tissue measuring device. Transmission electron microscopy and the TdT-mediated dUTP-biotin nick end labeling (TUNEL) methods were used as indices of apoptosis. Maximal BMG values were obtained 24 hours after ischemia when injury in the proximal tubular epithelium was most prominent. The maximal number of PCNA and BrdU-positive cells were obtained 24 hours after ischemia and thereafter gradually decreased. The n/BM index in the disorder group was significantly increased 96 hours and 1 week after ischemia (p < 0.001). Electron microscopy revealed nuclear fragmentation and apoptosis in the tubular area indicating that there were significant differences. The number of positive cells for in situ nick end labelling increased 24 hours and 2 weeks after ischemia, exhibiting a two peak curve. However, the number of positive cells significantly decreased 4 weeks after ischemia. In the proximal kidney tubules damaged by reperfusion after ischemia, epithelial hyperplasia developed 3 to 6 days after the most active period of S-phase cells was noted. Thereafter, a decreasing number of epithelial cells was observed. It seemed that the decreasing number of these cells had been produced by apoptosis detected 2 weeks after ischemia.
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PMID:[A pathomorphological study on damage and repair process of tubuli after renal ischemia]. 895 3

Proliferation and dedifferentiation of tubular cells are the hallmark of early regeneration after renal ischemic injury. Vimentin, a class III intermediate filament expressed only in mesenchymal cells of mature mammals, was shown to be transiently expressed in post-ischemic renal tubular epithelial cells. Vimentin re-expression was interpreted as a marker of cellular dedifferentiation, but its role in tubular regeneration after renal ischemia has also been hypothesized. This role was evaluated in mice bearing a null mutation of the vimentin gene. Expression of vimentin, proliferating cell nuclear antigen (a marker of cellular proliferation), and villin (a marker of differentiated brush-border membranes) was studied in wild-type (Vim+/+), heterozygous (Vim+/-), and homozygous (Vim-/-) mice subjected to transient ischemia of the left kidney. As expected, vimentin was detected by immunohistochemistry at the basal pole of proximal tubular cells from post-ischemic kidney in Vim+/+ and Vim+/- mice from day 2 to day 28. The expression of the reporter gene beta-galactosidase in Vim+/- and Vim-/- mice confirmed the tubular origin of vimentin. No compensatory expression of keratin could be demonstrated in Vim-/- mice. The intensity of proliferating cell nuclear antigen labeling and the pattern of villin expression were comparable in Vim-/-, Vim+/- and Vim+/+ mice at any time of the study. After 60 days, the structure of post-ischemic kidneys in Vim-/- mice was indistinguishable from that of normal non-operated kidneys in Vim+/+ mice. In conclusion, 1) the pattern of post-ischemic proximal tubular cell proliferation, differentiation, and tubular organization was not impaired in mice lacking vimentin and 2) these results suggest that the transient tubular expression of vimentin is not instrumental in tubular regeneration after renal ischemic injury.
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PMID:Normal tubular regeneration and differentiation of the post-ischemic kidney in mice lacking vimentin. 909 92

The present studies determined the effect of renal ischemia/reperfusion on components of the intrarenal renin-angiotensin system in rats and evaluated the effect of AT1 angiotensin (ANG) II receptor blockade on functional recovery. After bilateral renal pedicle occlusion for 60 min, serum creatinine increased, peaking at 72 h, and returned to sham levels after 120 h. ANG II levels in ischemic kidneys were significantly increased 24 h after reperfusion but did not differ from levels in sham kidneys after 120 h. Both renal cortical angiotensinogen mRNA and proximal tubular AT1 receptor mRNA were significantly reduced early after reperfusion, returning to sham levels by 120 and 72 h, respectively. AT2 ANG II receptor mRNA was undetectable in proximal tubules from sham rats but was consistently present in ischemic rats at 120 h. By histoautoradiography, we found that binding of 125I-labeled ANG II was preserved in glomeruli but was decreased in whole cortex and outer medulla early after reperfusion and was completely blocked by the AT1 antagonist losartan. Treatment of rats with losartan (25 mg/kg s.c. daily), starting at the time of reperfusion, had no effect on expression of proliferating cell nuclear antigen in cortical tubules but caused a significant decrease in serum creatinine at 72 h (ischemia: 334 +/- 69 microM vs. ischemia + losartan: 135 +/- 28 microM; P < 0.025, n = 6). These data indicate that renal ischemic injury causes an early increase in intrarenal ANG II levels, associated with reduction of mRNA for angiotensinogen and proximal tubular AT1 receptors, and maintenance of glomerular ANG II binding. Losartan accelerates recovery of renal function, suggesting that activation of AT1 receptors impairs glomerular filtration in the postischemic kidney.
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PMID:Role of AT1 angiotensin II receptors in renal ischemic injury. 945 26

Reactive oxygen species (ROS) contribute to the ischemia-reperfusion injury. In kidney, the intracellular sources of ROS during ischemia-reperfusion are still unclear. In the present study, we investigated the role of the catecholamine-degrading enzyme monoamine oxidases (MAOs) in hydrogen peroxide (H2O2) generation after reperfusion and their involvement in cell events leading to tissue injury and recovery. In a rat model of renal ischemia-reperfusion, we show concomitant MAO-dependent H2O2 production and lipid peroxidation in the early reperfusion period. Rat pretreatment with the irreversible MAO inhibitor pargyline resulted in the following: i) prevented H2O2 production and lipid peroxidation; ii) decreased tubular cell apoptosis and necrosis, measured by TUNEL staining and histomorphological criteria; and iii) increased tubular cell proliferation as determined by proliferating cell nuclear antigen expression. MAO inhibition also prevented Jun N-terminal kinase phosphorylation and promoted extracellular signal-regulated kinase activation, two mitogen-activated protein kinases described as a part of a "death" and "survival" pathway after ischemia-reperfusion. This work demonstrates the crucial role of MAOs in mediating the production of injurious ROS, which contribute to acute apoptotic and necrotic cell death induced by renal ischemia-reperfusion in vivo. Targeted inhibition of these oxidases could provide a new avenue for therapy to prevent renal damage and promote renal recovery after ischemia-reperfusion.
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PMID:Regulation of JNK/ERK activation, cell apoptosis, and tissue regeneration by monoamine oxidases after renal ischemia-reperfusion. 1203 44

Acute renal failure (ARF) secondary to ischemic injury remains a common and potentially devastating problem. A transcriptome-wide interrogation strategy was used to identify renal genes that are induced very early after renal ischemia, whose protein products might serve as novel biomarkers for ARF. Seven genes that are upregulated >10-fold were identified, one of which (Cyr61) has recently been reported to be induced after renal ischemia. Unexpectedly, the induction of the other six transcripts was novel to the ARF field. In this study, one of these previously unrecognized genes was further characterized, namely neutrophil gelatinase-associated lipocalin (NGAL), because it is a small secreted polypeptide that is protease resistant and consequently might be readily detected in the urine. The marked upregulation of NGAL mRNA and protein levels in the early postischemic mouse kidney was confirmed. NGAL protein expression was detected predominantly in proliferating cell nuclear antigen-positive proximal tubule cells, in a punctate cytoplasmic distribution that co-localized with markers of late endosomes. NGAL was easily detected in the urine in the very first urine output after ischemia in both mouse and rat models of ARF. The appearance of NGAL in the urine was related to the dose and duration of renal ischemia and preceded the appearance of other urinary markers such as N-acetyl-beta-D-glucosaminidase and beta2-microglobulin. The origin of NGAL from tubule cells was confirmed in cultured human proximal tubule cells subjected to in vitro ischemic injury, where NGAL mRNA was rapidly induced in the cells and NGAL protein was readily detectable in the culture medium within 1 h of mild ATP depletion. NGAL was also easily detectable in the urine of mice with cisplatin-induced nephrotoxicity, again preceding the appearance of N-acetyl-beta-D-glucosaminidase and beta2-microglobulin. The results indicate that NGAL may represent an early, sensitive, noninvasive urinary biomarker for ischemic and nephrotoxic renal injury.
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PMID:Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. 1451 31

The present study was conducted to explore renal progenitor-like cells that are actively engaged in tubular regeneration after injury. For addressing this issue, the existence of label-retaining cells (LRC; slow-cycling cells) in normal rat kidneys by in vivo bromodeoxyuridine (BrdU) labeling was examined. LRC were scattering among renal epithelial tubular cells of normal rat kidneys. During the recovery after renal ischemia, LRC underwent cell division and most of them became positive for proliferating cell nuclear antigen. In contrast, proliferating cell nuclear antigen-positive but BrdU-negative tubular cells were rarely observed, suggesting that cells proliferating during tubular regeneration are essentially derived from LRC. At an early phase of tubular regeneration, descendants of LRC expressed a mesenchymal marker, vimentin, and eventually became positive for an epithelial marker, E-cadherin, after multiple cell divisions. These findings suggested that LRC function as a source of regenerating cells to replace injured cells. Collectively, it was concluded that LRC are renal progenitor-like tubular cells that provide regenerating cells, which actively proliferate and eventually differentiate into epithelial cell, during tubular regeneration. It may be possible to regenerate renal tubules in vivo through the activation of LRC.
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PMID:Identification of renal progenitor-like tubular cells that participate in the regeneration processes of the kidney. 1463 29

The aim of this study was to determine the effect of rapamycin on renal ischemia-reperfusion injury (IRI) in mice. Renal IRI was induced in male BALB/c mice by clamping both renal pedicles for 45 min. The mice were treated with either vehicle or rapamycin (2 mg/kg/day) by oral gavage, starting 1 day before the IRI and continued daily till killing. The mice were killed on days 1, 3 and 7 after the operation. The severity of the renal IRI was assessed by serum creatinine levels and renal histology. Proliferation of renal tubular cells was quantified by immunohistochemical staining for proliferating cell nuclear antigen (PCNA). One day after the IRI, the serum creatinine levels of rapamycin-treated mice were significantly higher than those of the vehicle-treated mice. Kidney sections from rapamycin-treated mice showed more marked tubular damage and significantly lower number of PCNA-positive cells. The number of PCNA-positive cells in the rapamycin-treated mice remained significantly lower on day 3 after the IRI. By day 7 after the IRI, the serum creatinine levels, renal histology and positive PCNA staining in the kidney sections became similar between the two treatment groups. We conclude that in this murine model of renal IRI, rapamycin treatment aggravates renal IRI during the first 3 days after the insult. This effect might be mediated, at least partly, through inhibition of renal tubular cell proliferation.
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PMID:Effect of rapamycin on renal ischemia-reperfusion injury in mice. 1696 76


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